Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2019

Open Access 01-12-2019 | NSCLC | Review

AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications

Authors: Chenjing Zhu, Yuquan Wei, Xiawei Wei

Published in: Molecular Cancer | Issue 1/2019

Login to get access

Abstract

Molecular targeted therapy for cancer has been a research hotspot for decades. AXL is a member of the TAM family with the high-affinity ligand growth arrest-specific protein 6 (GAS6). The Gas6/AXL signalling pathway is associated with tumour cell growth, metastasis, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, drug resistance, immune regulation and stem cell maintenance. Different therapeutic agents targeting AXL have been developed, typically including small molecule inhibitors, monoclonal antibodies (mAbs), nucleotide aptamers, soluble receptors, and several natural compounds. In this review, we first provide a comprehensive discussion of the structure, function, regulation, and signalling pathways of AXL. Then, we highlight recent strategies for targeting AXL in the treatment of cancer.AXL-targeted drugs, either as single agents or in combination with conventional chemotherapy or other small molecule inhibitors, are likely to improve the survival of many patients. However, future investigations into AXL molecular signalling networks and robust predictive biomarkers are warranted to select patients who could receive clinical benefit and to avoid potential toxicities.
Literature
1.
Ko YJ, Small EJ, Kabbinavar F, Chachoua A, Taneja S, Reese D, DePaoli A, Hannah A, Balk SP, Bubley GJ. A multi-institutional phase ii study of SU101, a platelet-derived growth factor receptor inhibitor, for patients with hormone-refractory prostate cancer. Clin Cancer Res. 2001;7(4):800–5.PubMed
2.
Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99.PubMedCrossRef
3.
Subbiah V, Meyer C, Zinner R, Meric-Bernstam F, Zahurak ML, O'Connor A, Roszik J, Shaw K, Ludwig JA, Kurzrock R, et al. Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma. Clin Cancer Res. 2017;23(15):4027–34.PubMedPubMedCentralCrossRef
4.
5.
Feneyrolles C, Spenlinhauer A, Guiet L, Fauvel B, Dayde-Cazals B, Warnault P, Cheve G, Yasri A. Axl kinase as a key target for oncology: focus on small molecule inhibitors. Mol Cancer Ther. 2014;13(9):2141–8.PubMedCrossRef
6.
Barata PC, Rini BI. Treatment of renal cell carcinoma: Current status and future directions. CA Cancer J Clin. 2017;67(6):507–24.PubMedCrossRef
7.
8.
Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014;14(12):769–85.PubMedCrossRef
9.
Yamagata M, Sanes JR, Weiner JA. Synaptic adhesion molecules. Curr Opin Cell Biol. 2003;15(5):621–32.PubMedCrossRef
10.
Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35–83.PubMedPubMedCentralCrossRef
11.
Kimani SG, Kumar S, Bansal N, Singh K, Kholodovych V, Comollo T, Peng Y, Kotenko SV, Sarafianos SG, Bertino JR, et al. Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity. Sci Rep. 2017;7:43908.PubMedPubMedCentralCrossRef
12.
Toledo RA, Qin Y, Cheng ZM, Gao Q, Iwata S, Silva GM, Prasad ML, Ocal IT, Rao S, Aronin N, et al. Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas. Clin Cancer Res. 2016;22(9):2301–10.PubMedCrossRef
13.
Bellosta P, Costa M, Lin DA, Basilico C. The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding. Mol Cell Biol. 1995;15(2):614–25.PubMedPubMedCentralCrossRef
14.
Prasad D, Rothlin CV, Burrola P, Burstyn-Cohen T, Lu Q. Garcia de Frutos P, Lemke G: TAM receptor function in the retinal pigment epithelium. Mol Cell Neurosci. 2006;33(1):96–108.PubMedCrossRef
15.
Mark MR, Scadden DT, Wang Z, Gu Q, Goddard A. Godowski PJ: rse, a novel receptor-type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain. J Biol Chem. 1994;269(14):10720–8.PubMed
16.
Lu Q, Lemke G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science. 2001;293(5528):306–11.PubMedCrossRef
17.
Lai C, Gore M, Lemke G. Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase. Oncogene. 1994;9(9):2567–78.PubMed
18.
Katagiri M, Hakeda Y, Chikazu D, Ogasawara T, Takato T, Kumegawa M, Nakamura K, Kawaguchi H. Mechanism of stimulation of osteoclastic bone resorption through Gas6/Tyro 3, a receptor tyrosine kinase signaling, in mouse osteoclasts. J Biol Chem. 2001;276(10):7376–82.PubMedCrossRef
19.
Gal-Moscovici A, Scherzer P, Rubinger D, Weiss R, Dranitzki-Elhalel M, Popovtzer MM. Stimulation of osteoclastic bone resorption in a model of glycerol-induced acute renal failure: evidence for a parathyroid hormone-independent mechanism. Bone. 2002;31(4):488–91.PubMedCrossRef
20.
Angelillo-Scherrer A, de Frutos P, Aparicio C, Melis E, Savi P, Lupu F, Arnout J, Dewerchin M, Hoylaerts M, Herbert J, et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med. 2001;7(2):215–21.PubMedCrossRef
21.
Scaltriti M, Elkabets M, Baselga J. Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy. Clin Cancer Res. 2016;22(6):1313–7.PubMedPubMedCentralCrossRef
22.
Meertens L, Labeau A, Dejarnac O, Cipriani S, Sinigaglia L, Bonnet-Madin L, Le Charpentier T, Hafirassou ML, Zamborlini A, Cao-Lormeau VM, et al. Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses. Cell Rep. 2017;18(2):324–33.PubMedCrossRef
23.
Fujimori T, Grabiec AM, Kaur M, Bell TJ, Fujino N, Cook PC, Svedberg FR, MacDonald AS, Maciewicz RA, Singh D, et al. The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung. Mucosal Immunol. 2015;8(5):1021–30.PubMedPubMedCentralCrossRef
24.
Mudduluru G, Leupold JH, Stroebel P, Allgayer H. PMA up-regulates the transcription of Axl by AP-1 transcription factor binding to TRE sequences via the MAPK cascade in leukaemia cells. Biol Cell. 2010;103(1):21–33.PubMedCrossRef
25.
Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN, LaGory EL, Kariolis MS, Chan A, Lindgren D, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014;111(37):13373–8.PubMedPubMedCentralCrossRef
26.
Mudduluru G, Vajkoczy P, Allgayer H. Myeloid zinc finger 1 induces migration, invasion, and in vivo metastasis through Axl gene expression in solid cancer. Mol Cancer Res. 2010;8(2):159–69.PubMedCrossRef
27.
Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell. 2007;131(6):1124–36.PubMedCrossRef
28.
29.
Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Luthar N, Toulany M, Gill PS, Salgia R, Kimple RJ, et al. AXL mediates resistance to cetuximab therapy. Cancer Res. 2014;74(18):5152–64.PubMedPubMedCentralCrossRef
30.
Yeh CY, Shin SM, Yeh HH, Wu TJ, Shin JW, Chang TY, Raghavaraju G, Lee CT, Chiang JH, Tseng VS, et al. Transcriptional activation of the Axl and PDGFR-alpha by c-Met through a ras- and Src-independent mechanism in human bladder cancer. BMC Cancer. 2011;11:139.PubMedPubMedCentralCrossRef
31.
Mudduluru G, Ceppi P, Kumarswamy R, Scagliotti GV, Papotti M, Allgayer H. Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer. Oncogene. 2011;30(25):2888–99.PubMedCrossRef
32.
Li R, Shi X, Ling F, Wang C, Liu J, Wang W, Li M. MiR-34a suppresses ovarian cancer proliferation and motility by targeting AXL. Tumour Biol. 2015;36(9):7277–83.PubMedCrossRef
33.
Ott M, Litzenburger UM, Sahm F, Rauschenbach KJ, Tudoran R, Hartmann C, Marquez VE, von Deimling A, Wick W, Platten M. Promotion of glioblastoma cell motility by enhancer of zeste homolog 2 (EZH2) is mediated by AXL receptor kinase. PLoS One. 2012;7(10):e47663.PubMedPubMedCentralCrossRef
34.
Mudduluru G, Allgayer H. The human receptor tyrosine kinase Axl gene--promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008;28(3):161–76.PubMedCrossRef
35.
Valverde P. Effects of Gas6 and hydrogen peroxide in Axl ubiquitination and downregulation. Biochem Biophys Res Commun. 2005;333(1):180–5.PubMedCrossRef
36.
Sather S, Kenyon KD, Lefkowitz JB, Liang X, Varnum BC, Henson PM, Graham DK. A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. Blood. 2007;109(3):1026–33.PubMedPubMedCentralCrossRef
37.
O'Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R 3rd, Le Beau MM, Earp HS, Liu ET. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol. 1991;11(10):5016–31.PubMedPubMedCentralCrossRef
38.
Lu Q, Gore M, Zhang Q, Camenisch T, Boast S, Casagranda F, Lai C, Skinner MK, Klein R, Matsushima GK, et al. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature. 1999;398(6729):723–8.PubMedCrossRef
39.
Mosesson Y, Shtiegman K, Katz M, Zwang Y, Vereb G, Szollosi J, Yarden Y. Endocytosis of receptor tyrosine kinases is driven by monoubiquitylation, not polyubiquitylation. J Biol Chem. 2003;278(24):21323–6.PubMedCrossRef
40.
Vajkoczy P, Knyazev P, Kunkel A, Capelle HH, Behrndt S, von Tengg-Kobligk H, Kiessling F, Eichelsbacher U, Essig M, Read TA, et al. Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci U S A. 2006;103(15):5799–804.PubMedPubMedCentralCrossRef
41.
Funakoshi H, Yonemasu T, Nakano T, Matumoto K, Nakamura T. Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons. J Neurosci Res. 2002;68(2):150–60.PubMedCrossRef
42.
Kanlikilicer P, Ozpolat B, Aslan B, Bayraktar R, Gurbuz N, Rodriguez-Aguayo C, Bayraktar E, Denizli M, Gonzalez-Villasana V, Ivan C, et al. Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models. Mol Ther Nucleic Acids. 2017;9:251–62.PubMedPubMedCentralCrossRef
43.
Onken J, Torka R, Korsing S, Radke J, Krementeskaia I, Nieminen M, Bai X, Ullrich A, Heppner F, Vajkoczy P. Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo. Oncotarget. 2016;7(9):9876–89.PubMedPubMedCentralCrossRef
44.
Hsieh MS, Yang PW, Wong LF, Lee JM. The AXL receptor tyrosine kinase is associated with adverse prognosis and distant metastasis in esophageal squamous cell carcinoma. Oncotarget. 2016;7(24):36956–70.PubMedPubMedCentralCrossRef
45.
Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, Lai GM, Chuang SE. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 2008;268(2):314–24.PubMedCrossRef
46.
Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W, Duan M, Torneros A, Yu J, Heckrodt TJ, et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010;70(4):1544–54.PubMedCrossRef
47.
Gjerdrum C, Tiron C, Hoiby T, Stefansson I, Haugen H, Sandal T, Collett K, Li S, McCormack E, Gjertsen BT, et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. 2010;107(3):1124–9.PubMedCrossRef
48.
Elkabets M, Pazarentzos E, Juric D, Sheng Q, Pelossof RA, Brook S, Benzaken AO, Rodon J, Morse N, Yan JJ, et al. AXL mediates resistance to PI3Kalpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell. 2015;27(4):533–46.PubMedPubMedCentralCrossRef
49.
Dufies M, Jacquel A, Belhacene N, Robert G, Cluzeau T, Luciano F, Cassuto JP, Raynaud S, Auberger P. Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells. Oncotarget. 2011;2(11):874–85.PubMedPubMedCentralCrossRef
50.
Dransfield I, Farnworth S. Axl and Mer Receptor Tyrosine Kinases: Distinct and Nonoverlapping Roles in Inflammation and Cancer? Adv Exp Med Biol. 2016;930:113–32.PubMedCrossRef
51.
Debruyne DN, Bhatnagar N, Sharma B, Luther W, Moore NF, Cheung NK, Gray NS, George RE. ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT. Oncogene. 2016;35(28):3681–91.PubMedCrossRef
52.
Corno C, Gatti L, Lanzi C, Zaffaroni N, Colombo D, Perego P. Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells. Curr Med Chem. 2016;23(15):1496–512.PubMedCrossRef
53.
Burchert A, Attar EC, McCloskey P, Fridell YW, Liu ET. Determinants for transformation induced by the Axl receptor tyrosine kinase. Oncogene. 1998;16(24):3177–87.PubMedCrossRef
54.
Balaji K, Vijayaraghavan S, Diao L, Tong P, Fan Y, Carey JP, Bui TN, Warner S, Heymach JV, Hunt KK, et al. AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers. Mol Cancer Res. 2017;15(1):45–58.PubMedCrossRef
55.
Maacha S, Hong J, von Lersner A, Zijlstra A, Belkhiri A. AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking. Neoplasia. 2018;20(10):1008–22.PubMedPubMedCentralCrossRef
56.
57.
58.
59.
Varnum BC, Young C, Elliott G, Garcia A, Bartley TD, Fridell YW, Hunt RW, Trail G, Clogston C, Toso RJ, et al. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature. 1995;373(6515):623–6.PubMedCrossRef
60.
Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Gohring W, Ullrich A, Timpl R, Hohenester E. Structural basis for Gas6-Axl signalling. EMBO J. 2006;25(1):80–7.PubMedCrossRef
61.
Braunger J, Schleithoff L, Schulz AS, Kessler H, Lammers R, Ullrich A, Bartram CR, Janssen JW. Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site. Oncogene. 1997;14(22):2619–31.PubMedCrossRef
62.
Fridell YW, Jin Y, Quilliam LA, Burchert A, McCloskey P, Spizz G, Varnum B, Der C, Liu ET. Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase. Mol Cell Biol. 1996;16(1):135–45.PubMedPubMedCentralCrossRef
63.
64.
Huang H, Liu H, Yan R, Hu M. PI3K/Akt and ERK/MAPK Signaling Promote Different Aspects of Neuron Survival and Axonal Regrowth Following Rat Facial Nerve Axotomy. Neurochem Res. 2017;42(12):3515–24.PubMedCrossRef
65.
Sen T, Tong P, Diao L, Li L, Fan Y, Hoff J, Heymach JV, Wang J, Byers LA. Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer. Clin Cancer Res. 2017;23(20):6239–53.PubMedPubMedCentralCrossRef
66.
Kariolis MS, Miao YR, Diep A, Nash SE, Olcina MM, Jiang D, Jones DS 2nd, Kapur S. Mathews, II, Koong AC et al: Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. J Clin Invest. 2017;127(1):183–98.PubMedCrossRef
67.
Meyer AS, Miller MA, Gertler FB, Lauffenburger DA. The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells. Sci Signal. 2013;6(287):ra66.PubMedPubMedCentralCrossRef
68.
Vouri M, Croucher DR, Kennedy SP, An Q, Pilkington GJ, Hafizi S. Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells. Oncogenesis. 2016;5(10):e266.PubMedPubMedCentralCrossRef
69.
May CD, Garnett J, Ma X, Landers SM, Ingram DR, Demicco EG, Al Sannaa GA, Vu T, Han L, Zhang Y, et al. AXL is a potential therapeutic target in dedifferentiated and pleomorphic liposarcomas. BMC Cancer. 2015;15:901.PubMedPubMedCentralCrossRef
70.
Hasanbasic I, Cuerquis J, Varnum B, Blostein MD. Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells. Am J Physiol Heart Circ Physiol. 2004;287(3):H1207–13.PubMedCrossRef
71.
Han J, Tian R, Yong B, Luo C, Tan P, Shen J, Peng T. Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients. Biochem Biophys Res Commun. 2013;435(3):493–500.PubMedCrossRef
72.
Sinha S, Boysen J, Nelson M, Secreto C, Warner SL, Bearss DJ, Lesnick C, Shanafelt TD, Kay NE, Ghosh AK. Targeted Axl Inhibition Primes Chronic Lymphocytic Leukemia B Cells to Apoptosis and Shows Synergistic/Additive Effects in Combination with BTK Inhibitors. Clin Cancer Res. 2015;21(9):2115–26.PubMedPubMedCentralCrossRef
73.
Bell JB, Eckerdt FD, Alley K, Magnusson LP, Hussain H, Bi Y, Arslan AD, Clymer J, Alvarez AA, Goldman S, et al. MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma. Mol Cancer Res. 2016;14(10):984–93.PubMedPubMedCentralCrossRef
74.
Sainaghi PP, Castello L, Bergamasco L, Galletti M, Bellosta P, Avanzi GC. Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. J Cell Physiol. 2005;204(1):36–44.PubMedCrossRef
75.
Yuen HF, McCrudden CM, Huang YH, Tham JM, Zhang X, Zeng Q, Zhang SD, Hong W. TAZ expression as a prognostic indicator in colorectal cancer. PLoS One. 2013;8(1):e54211.PubMedPubMedCentralCrossRef
76.
Koorstra JB, Karikari CA, Feldmann G, Bisht S, Rojas PL, Offerhaus GJ, Alvarez H, Maitra A. The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biol Ther. 2009;8(7):618–26.PubMedCrossRef
77.
Lay JD, Hong CC, Huang JS, Yang YY, Pao CY, Liu CH, Lai YP, Lai GM, Cheng AL, Su IJ, et al. Sulfasalazine suppresses drug resistance and invasiveness of lung adenocarcinoma cells expressing AXL. Cancer Res. 2007;67(8):3878–87.PubMedCrossRef
78.
Tai KY, Shieh YS, Lee CS, Shiah SG, Wu CW. Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg-1. Oncogene. 2008;27(29):4044–55.PubMedCrossRef
79.
Zhang YX, Knyazev PG, Cheburkin YV, Sharma K, Knyazev YP, Orfi L, Szabadkai I, Daub H, Keri G, Ullrich A. AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res. 2008;68(6):1905–15.PubMedCrossRef
80.
Xu MZ, Chan SW, Liu AM, Wong KF, Fan ST, Chen J, Poon RT, Zender L, Lowe SW, Hong W, et al. AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma. Oncogene. 2011;30(10):1229–40.PubMedCrossRef
81.
Rankin EB, Fuh KC, Taylor TE, Krieg AJ, Musser M, Yuan J, Wei K, Kuo CJ, Longacre TA, Giaccia AJ. AXL is an essential factor and therapeutic target for metastatic ovarian cancer. Cancer Res. 2010;70(19):7570–9.PubMedPubMedCentralCrossRef
82.
Demarchi F, Verardo R, Varnum B, Brancolini C, Schneider C. Gas6 anti-apoptotic signaling requires NF-kappa B activation. J Biol Chem. 2001;276(34):31738–44.PubMedCrossRef
83.
Wang X, Saso H, Iwamoto T, Xia W, Gong Y, Pusztai L, Woodward WA, Reuben JM, Warner SL, Bearss DJ, et al. TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase. Cancer Res. 2013;73(21):6516–25.PubMedPubMedCentralCrossRef
84.
Leconet W, Chentouf M, du Manoir S, Chevalier C, Sirvent A, Ait-Arsa I, Busson M, Jarlier M, Radosevic-Robin N, Theillet C, et al. Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis. Clin Cancer Res. 2017;23(11):2806–16.PubMedCrossRef
85.
Avilla E, Guarino V, Visciano C, Liotti F, Svelto M, Krishnamoorthy G, Franco R, Melillo RM. Activation of TYRO3/AXL tyrosine kinase receptors in thyroid cancer. Cancer Res. 2011;71(5):1792–804.PubMedCrossRef
86.
Li Y, Ye X, Tan C, Hongo JA, Zha J, Liu J, Kallop D, Ludlam MJ, Pei L. Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene. 2009;28(39):3442–55.PubMedCrossRef
87.
Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS, Wu CW. Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia. 2005;7(12):1058–64.PubMedPubMedCentralCrossRef
88.
Chen T, You Y, Jiang H, Wang ZZ. Epithelial-mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis. J Cell Physiol. 2017;232(12):3261–72.PubMedPubMedCentralCrossRef
89.
Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 2009;119(6):1438–49.PubMedPubMedCentralCrossRef
90.
91.
Nieto MA. Epithelial-Mesenchymal Transitions in development and disease: old views and new perspectives. Int J Dev Biol. 2009;53(8–10):1541–7.PubMedCrossRef
92.
93.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.PubMedCrossRef
94.
Goyette MA, Duhamel S, Aubert L, Pelletier A, Savage P, Thibault MP, Johnson RM, Carmeliet P, Basik M, Gaboury L, et al. The Receptor Tyrosine Kinase AXL Is Required at Multiple Steps of the Metastatic Cascade during HER2-Positive Breast Cancer Progression. Cell Rep. 2018;23(5):1476–90.PubMedCrossRef
95.
Cichon MA, Szentpetery Z, Caley MP, Papadakis ES, Mackenzie IC, Brennan CH, O'Toole EA. The receptor tyrosine kinase Axl regulates cell-cell adhesion and stemness in cutaneous squamous cell carcinoma. Oncogene. 2014;33(32):4185–92.PubMedCrossRef
96.
Asiedu MK, Beauchamp-Perez FD, Ingle JN, Behrens MD, Radisky DC, Knutson KL. AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells. Oncogene. 2014;33(10):1316–24.PubMedCrossRef
97.
Singh M, Yelle N, Venugopal C, Singh SK. EMT: Mechanisms and therapeutic implications. Pharmacol Ther. 2018;182:80–94.PubMedCrossRef
98.
Lin JZ, Wang ZJ, De W, Zheng M, Xu WZ, Wu HF, Armstrong A, Zhu JG. Targeting AXL overcomes resistance to docetaxel therapy in advanced prostate cancer. Oncotarget. 2017;8(25):41064–77.PubMedPubMedCentral
99.
100.
Fridell YW, Villa J Jr, Attar EC, Liu ET. GAS6 induces Axl-mediated chemotaxis of vascular smooth muscle cells. J Biol Chem. 1998;273(12):7123–6.PubMedCrossRef
101.
Ramjiawan RR, Griffioen AW, Duda DG. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis. 2017;20(2):185–204.PubMedPubMedCentralCrossRef
102.
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.CrossRefPubMed
103.
104.
Ruan GX, Kazlauskas A. Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis. J Biol Chem. 2013;288(29):21161–72.PubMedPubMedCentralCrossRef
105.
Holland SJ, Powell MJ, Franci C, Chan EW, Friera AM, Atchison RE, McLaughlin J, Swift SE, Pali ES, Yam G, et al. Multiple roles for the receptor tyrosine kinase axl in tumor formation. Cancer Res. 2005;65(20):9294–303.PubMedCrossRef
106.
Pinato DJ, Chowdhury S, Stebbing J. TAMing resistance to multi-targeted kinase inhibitors through Axl and Met inhibition. Oncogene. 2016;35(21):2684–6.PubMedCrossRef
107.
Linger RM, Keating AK, Earp HS, Graham DK. Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors. Expert Opin Ther Targets. 2010;14(10):1073–90.PubMedPubMedCentralCrossRef
108.
Gallicchio M, Mitola S, Valdembri D, Fantozzi R, Varnum B, Avanzi GC, Bussolino F. Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood. 2005;105(5):1970–6.PubMedCrossRef
109.
110.
Ben-Batalla I, Erdmann R, Jorgensen H, Mitchell R, Ernst T, von Amsberg G, Schafhausen P, Velthaus JL, Rankin S, Clark RE, et al. Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia. Clin Cancer Res. 2017;23(9):2289–300.PubMedCrossRef
111.
Schoumacher M, Burbridge M. Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies. Curr Oncol Rep. 2017;19(3):19.PubMedPubMedCentralCrossRef
112.
Kim KC, Baek SH, Lee C. Curcumin-induced downregulation of Axl receptor tyrosine kinase inhibits cell proliferation and circumvents chemoresistance in non-small lung cancer cells. Int J Oncol. 2015;47(6):2296–303.PubMedCrossRef
113.
Heckmann D, Maier P, Laufs S, Li L, Sleeman JP, Trunk MJ, Leupold JH, Wenz F, Zeller WJ, Fruehauf S, et al. The disparate twins: a comparative study of CXCR4 and CXCR7 in SDF-1alpha-induced gene expression, invasion and chemosensitivity of colon cancer. Clin Cancer Res. 2014;20(3):604–16.PubMedCrossRef
114.
Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Coan JP, Pearson HE, Bahrar H, Fowler TL, Bednarz BP, et al. AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2015;21(11):2601–12.PubMedPubMedCentralCrossRef
115.
Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, Berent-Maoz B, Pang J, Chmielowski B, Cherry G, et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell. 2016;165(1):35–44.PubMedPubMedCentralCrossRef
116.
Giles KM, Kalinowski FC, Candy PA, Epis MR, Zhang PM, Redfern AD, Stuart LM, Goodall GJ, Leedman PJ. Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib. Mol Cancer Ther. 2013;12(11):2541–58.PubMedCrossRef
117.
Tian Y, Zhang Z, Miao L, Yang Z, Yang J, Wang Y, Qian D, Cai H, Wang Y. Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells. Oncol Res. 2016;24(5):295–303.PubMedCrossRefPubMedCentral
118.
Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K, Wisner L, Iorio M, Shakalya K, Garewal H, et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007;26(27):3909–19.PubMedCrossRef
119.
Shen Y, Chen X, He J, Liao D, Zu X. Axl inhibitors as novel cancer therapeutic agents. Life Sci. 2018;198:99–111.PubMedCrossRef
120.
Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A, Tanimoto A, Takeuchi S, Araujo LH, Boroni M, et al. AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells. Nat Commun. 2019;10(1):259.PubMedPubMedCentralCrossRef
121.
Macleod K, Mullen P, Sewell J, Rabiasz G, Lawrie S, Miller E, Smyth JF, Langdon SP. Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. Cancer Res. 2005;65(15):6789–800.PubMedCrossRef
122.
Skinner HD, Giri U, Yang LP, Kumar M, Liu Y, Story MD, Pickering CR, Byers LA, Williams MD, Wang J, et al. Integrative Analysis Identifies a Novel AXL-PI3 Kinase-PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer. Clin Cancer Res. 2017;23(11):2713–22.PubMedPubMedCentralCrossRef
123.
Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, Halsey W, Sathe GM, Martin AM, Gilmer TM. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 2009;69(17):6871–8.PubMedCrossRef
124.
125.
Kurowska-Stolarska M, Alivernini S, Melchor EG, Elmesmari A, Tolusso B, Tange C, Petricca L, Gilchrist DS, Di Sante G, Keijzer C, et al. MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis. Nat Commun. 2017;8:15877.PubMedPubMedCentralCrossRef
126.
Chan PY, Carrera Silva EA, De Kouchkovsky D, Joannas LD, Hao L, Hu D, Huntsman S, Eng C, Licona-Limon P, Weinstein JS, et al. The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science. 2016;352(6281):99–103.PubMedPubMedCentralCrossRef
127.
Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014;507(7493):508–12.PubMedPubMedCentralCrossRef
128.
Nguyen KQ, Tsou WI, Kotenko S, Birge RB. TAM receptors in apoptotic cell clearance, autoimmunity, and cancer. Autoimmunity. 2013;46(5):294–7.PubMedCrossRef
129.
Weinger JG, Brosnan CF, Loudig O, Goldberg MF, Macian F, Arnett HA, Prieto AL, Tsiperson V, Shafit-Zagardo B. Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during experimental autoimmune encephalomyelitis. J Neuroinflammation. 2011;8:49.PubMedPubMedCentralCrossRef
130.
Sharif MN, Sosic D, Rothlin CV, Kelly E, Lemke G, Olson EN, Ivashkiv LB. Twist mediates suppression of inflammation by type I IFNs and Axl. J Exp Med. 2006;203(8):1891–901.PubMedPubMedCentralCrossRef
131.
Bosurgi L, Bernink JH, Delgado Cuevas V, Gagliani N, Joannas L, Schmid ET, Booth CJ, Ghosh S, Rothlin CV. Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer. Proc Natl Acad Sci U S A. 2013;110(32):13091–6.PubMedPubMedCentralCrossRef
132.
Uribe DJ, Mandell EK, Watson A, Martinez JD, Leighton JA, Ghosh S, Rothlin CV. The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer. PLoS One. 2017;12(7):e0179979.PubMedPubMedCentralCrossRef
133.
Aguilera TA, Giaccia AJ. Molecular Pathways: Oncologic Pathways and Their Role in T-cell Exclusion and Immune Evasion-A New Role for the AXL Receptor Tyrosine Kinase. Clin Cancer Res. 2017;23(12):2928–33.PubMedPubMedCentralCrossRef
134.
135.
Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, Zhou A, Eyob H, Balakrishnan S, Wang CY, et al. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature. 2015;526(7571):131–5.PubMedPubMedCentralCrossRef
136.
Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17(5):548–58.PubMedCrossRef
137.
Jin Y, Nie D, Li J, Du X, Lu Y, Li Y, Liu C, Zhou J, Pan J. Gas6/AXL Signaling Regulates Self-Renewal of Chronic Myelogenous Leukemia Stem Cells by Stabilizing beta-Catenin. Clin Cancer Res. 2017;23(11):2842–55.PubMedCrossRef
138.
139.
Ye X, Li Y, Stawicki S, Couto S, Eastham-Anderson J, Kallop D, Weimer R, Wu Y, Pei L. An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene. 2010;29(38):5254–64.PubMedCrossRef
140.
Qi W, Cooke LS, Stejskal A, Riley C, Croce KD, Saldanha JW, Bearss D, Mahadevan D. MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer. BMC Cancer. 2009;9:142.PubMedPubMedCentralCrossRef
141.
Vultur A, Buettner R, Kowolik C, Liang W, Smith D, Boschelli F, Jove R. SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol Cancer Ther. 2008;7(5):1185–94.PubMedPubMedCentralCrossRef
142.
Dai Y, Siemann DW. BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro. Mol Cancer Ther. 2010;9(6):1554–61.PubMedCrossRef
143.
Myers SH, Brunton VG, Unciti-Broceta A. AXL Inhibitors in Cancer: A Medicinal Chemistry Perspective. J Med Chem. 2016;59(8):3593–608.PubMedCrossRef
144.
Zhao Z, Wu H, Wang L, Liu Y, Knapp S, Liu Q, Gray NS. Exploration of type II binding mode: A privileged approach for kinase inhibitor focused drug discovery? ACS Chem Biol. 2014;9(6):1230–41.PubMedPubMedCentralCrossRef
145.
Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011;29(11):1046–51.PubMedCrossRef
146.
Rodon J, Postel-Vinay S, Hollebecque A, Nuciforo P, Azaro A, Cattan V, Marfai L, Sudey I, Brendel K, Delmas A, et al. First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours. Eur J Cancer. 2017;81:142–50.PubMedCrossRef
147.
Tibes R, Fine G, Choy G, Redkar S, Taverna P, Oganesian A, Sahai A, Azab M, Tolcher AW. A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013;71(2):463–71.PubMedCrossRef
148.
Vergote IB, Smith DC, Berger R, Kurzrock R, Vogelzang NJ, Sella A, Wheler J, Lee Y, Foster PG, Weitzman R, et al. A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma. Eur J Cancer. 2017;83:229–36.PubMedCrossRef
149.
Daud A, Kluger HM, Kurzrock R, Schimmoller F, Weitzman AL, Samuel TA, Moussa AH, Gordon MS, Shapiro GI. Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma. Br J Cancer. 2017;116(4):432–40.PubMedPubMedCentralCrossRef
150.
Wakelee HA, Gettinger S, Engelman J, Janne PA, West H, Subramaniam DS, Leach J, Wax M, Yaron Y, Miles DR, et al. A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 2017;79(5):923–32.PubMedPubMedCentralCrossRef
151.
Leighl NB, Tsao MS, Liu G, Tu D, Ho C, Shepherd FA, Murray N, Goffin JR, Nicholas G, Sakashita S, et al. A phase I study of foretinib plus erlotinib in patients with previously treated advanced non-small cell lung cancer: Canadian cancer trials group IND.196. Oncotarget. 2017;8(41):69651–62.PubMedPubMedCentralCrossRef
152.
Shah MA, Wainberg ZA, Catenacci DV, Hochster HS, Ford J, Kunz P, Lee FC, Kallender H, Cecchi F, Rabe DC, et al. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS One. 2013;8(3):e54014.PubMedPubMedCentralCrossRef
153.
Rayson D, Lupichuk S, Potvin K, Dent S, Shenkier T, Dhesy-Thind S, Ellard SL, Prady C, Salim M, Farmer P, et al. Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer. Breast Cancer Res Treat. 2016;157(1):109–16.PubMedCrossRef
154.
Ghosh AK, Secreto C, Boysen J, Sassoon T, Shanafelt TD, Mukhopadhyay D, Kay NE. The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy. Blood. 2011;117(6):1928–37.PubMedPubMedCentralCrossRef
155.
Chen F, Song Q, Yu Q. Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition. Am J Cancer Res. 2018;8(8):1466–82.PubMedPubMedCentral
156.
Ben-Batalla I, Schultze A, Wroblewski M, Erdmann R, Heuser M, Waizenegger JS, Riecken K, Binder M, Schewe D, Sawall S, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood. 2013;122(14):2443–52.PubMedCrossRef
157.
Mollard A, Warner SL, Call LT, Wade ML, Bearss JJ, Verma A, Sharma S, Vankayalapati H, Bearss DJ. Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors. ACS Med Chem Lett. 2011;2(12):907–12.PubMedPubMedCentralCrossRef
158.
Jimenez L, Wang J, Morrison MA, Whatcott C, Soh KK, Warner S, Bearss D, Jette CA, Stewart RA. Phenotypic chemical screening using a zebrafish neural crest EMT reporter identifies retinoic acid as an inhibitor of epithelial morphogenesis. Dis Model Mech. 2016;9(4):389–400.PubMedPubMedCentralCrossRef
159.
Patel V, Keating MJ, Wierda WG, Gandhi V. Preclinical combination of TP-0903, an AXL inhibitor and B-PAC-1, a procaspase-activating compound with ibrutinib in chronic lymphocytic leukemia. Leuk Lymphoma. 2016;57(6):1494–7.PubMedCrossRef
160.
Aveic S, Corallo D, Porcu E, Pantile M, Boso D, Zanon C, Viola G, Sidarovich V, Mariotto E, Quattrone A, et al. TP-0903 inhibits neuroblastoma cell growth and enhances the sensitivity to conventional chemotherapy. Eur J Pharmacol. 2018;818:435–48.PubMedCrossRef
161.
Dantas-Barbosa C, Lesluyes T, Loarer FL, Chibon F, Treilleux I, Coindre JM, Meeus P, Brahmi M, Bally O, Ray-Coquard I, et al. Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma. Br J Cancer. 2017;117(12):1787–97.PubMedPubMedCentralCrossRef
162.
Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther. 2007;6(12 Pt 1):3314–22.PubMedCrossRef
163.
Sampson ER, Martin BA, Morris AE, Xie C, Schwarz EM, O'Keefe RJ, Rosier RN. The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model. J Bone Miner Res. 2011;26(6):1283–94.PubMedCrossRef
164.
Cullinane C, Dorow DS, Jackson S, Solomon B, Bogatyreva E, Binns D, Young R, Arango ME, Christensen JG, McArthur GA, et al. Differential (18)F-FDG and 3′-deoxy-3′-(18)F-fluorothymidine PET responses to pharmacologic inhibition of the c-MET receptor in preclinical tumor models. J Nucl Med. 2011;52(8):1261–7.PubMedCrossRef
165.
Gong HC, Wang S, Mayer G, Chen G, Leesman G, Singh S, Beer DG. Signatures of drug sensitivity in nonsmall cell lung cancer. Int J Proteomics. 2011;2011:215496.PubMedPubMedCentralCrossRef
166.
Blackhall F, Cappuzzo F. Crizotinib: from discovery to accelerated development to front-line treatment. Ann Oncol. 2016;27(Suppl 3):iii35–41.PubMedCrossRef
167.
Poon CC, Kelly JJ. Development of crizotinib, a rationally designed tyrosine kinase inhibitor for non-small cell lung cancer. Int J Cancer. 2017;140(9):1945–54.PubMedCrossRef
168.
Tucker ER, Danielson LS, Innocenti P, Chesler L. Tackling Crizotinib Resistance: The Pathway from Drug Discovery to the Pediatric Clinic. Cancer Res. 2015;75(14):2770–4.PubMedPubMedCentralCrossRef
169.
Boschelli DH, Ye F, Wang YD, Dutia M, Johnson SL, Wu B, Miller K, Powell DW, Yaczko D, Young M, et al. Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem. 2001;44(23):3965–77.PubMedCrossRef
170.
Lee HJ, Jeng YM, Chen YL, Chung L, Yuan RH. Gas6/Axl pathway promotes tumor invasion through the transcriptional activation of Slug in hepatocellular carcinoma. Carcinogenesis. 2014;35(4):769–75.PubMedCrossRef
171.
Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, Frost P, Ye F, Boschelli DH, Boschelli F. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003;63(2):375–81.PubMed
172.
Golas JM, Lucas J, Etienne C, Golas J, Discafani C, Sridharan L, Boghaert E, Arndt K, Ye F, Boschelli DH, et al. SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models. Cancer Res. 2005;65(12):5358–64.PubMedCrossRef
173.
Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, Zaritskey A, Countouriotis A, Besson N, Leip E, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119(15):3403–12.PubMedPubMedCentralCrossRef
174.
Garcia-Gutierrez V, Milojkovic D, Hernandez-Boluda JC, Claudiani S, Martin Mateos ML, Casado-Montero LF, Gonzalez G, Jimenez-Velasco A, Boque C, Martinez-Trillos A, et al. Safety and efficacy of bosutinib in fourth-line therapy of chronic myeloid leukemia patients. Ann Hematol. 2019;98(2):321–30.PubMedCrossRef
175.
Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Dyagil I, Glushko N, Milojkovic D, le Coutre P, et al. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol. 2018;36(3):231–7.PubMedCrossRef
176.
Park IK, Mishra A, Chandler J, Whitman SP, Marcucci G, Caligiuri MA. Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target. Blood. 2013;121(11):2064–73.PubMedPubMedCentralCrossRef
177.
Park IK, Mundy-Bosse B, Whitman SP, Zhang X, Warner SL, Bearss DJ, Blum W, Marcucci G, Caligiuri MA. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia. 2015;29(12):2382–9.PubMedCrossRefPubMedCentral
178.
Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R, Shimada I, Mori K, Kuromitsu S. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017;35(5):556–65.PubMedPubMedCentralCrossRef
179.
Usuki K, Sakura T, Kobayashi Y, Miyamoto T, Iida H, Morita S, Bahceci E, Kaneko M, Kusano M, Yamada S, et al. Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: An open-label phase 1 study. Cancer Sci. 2018;109(10):3235–44.PubMedPubMedCentralCrossRef
180.
Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol. 2017;18(8):1061–75.PubMedPubMedCentralCrossRef
181.
182.
Burbridge MF, Bossard CJ, Saunier C, Fejes I, Bruno A, Leonce S, Ferry G, Da Violante G, Bouzom F, Cattan V, et al. S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab. Mol Cancer Ther. 2013;12(9):1749–62.PubMedCrossRef
183.
Clemenson C, Chargari C, Liu W, Mondini M, Ferte C, Burbridge MF, Cattan V, Jacquet-Bescond A, Deutsch E. The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy. Mol Cancer Ther. 2017;16(10):2107–19.PubMedCrossRef
184.
Viteri S, Chang GC, Chiari R, Cho BC, Ciardiello F, Curigliano G, et al. Combination of the S49076 with gefitinib in NSCLC patients progressing on EGFR-TKI and harboring MET/AXL dysregulation. Ann Oncol. 2018;29.
185.
Zhao H, Luoto KR, Meng AX, Bristow RG. The receptor tyrosine kinase inhibitor amuvatinib (MP470) sensitizes tumor cells to radio- and chemo-therapies in part by inhibiting homologous recombination. Radiother Oncol. 2011;101(1):59–65.PubMedCrossRef
186.
Welsh JW, Mahadevan D, Ellsworth R, Cooke L, Bearss D, Stea B. The c-Met receptor tyrosine kinase inhibitor MP470 radiosensitizes glioblastoma cells. Radiat Oncol. 2009;4:69.PubMedPubMedCentralCrossRef
187.
Mahadevan D, Theiss N, Morales C, Stejskal AE, Cooke LS, Zhu M, Kurtzman D, Swart R, Ong E, Qi W. Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST). Oncotarget. 2015;6(4):1954–66.PubMedCrossRef
188.
Mita M, Gordon M, Rosen L, Kapoor N, Choy G, Redkar S, Taverna P, Oganesian A, Sahai A, Azab M, et al. Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors. Cancer Chemother Pharmacol. 2014;74(1):195–204.PubMedCrossRef
189.
Patyna S, Arrigoni C, Terron A, Kim TW, Heward JK, Vonderfecht SL, Denlinger R, Turnquist SE, Evering W. Nonclinical safety evaluation of sunitinib: a potent inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors. Toxicol Pathol. 2008;36(7):905–16.PubMedCrossRef
190.
Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, Fukuda JY, Chu JY, Nematalla A, Wang X, et al. Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem. 2003;46(7):1116–9.PubMedCrossRef
191.
Kitagawa D, Yokota K, Gouda M, Narumi Y, Ohmoto H, Nishiwaki E, Akita K, Kirii Y. Activity-based kinase profiling of approved tyrosine kinase inhibitors. Genes Cells. 2013;18(2):110–22.PubMedCrossRef
192.
Nassif E, Thibault C, Vano Y, Fournier L, Mauge L, Verkarre V, Timsit MO, Mejean A, Tartour E, Oudard S. Sunitinib in kidney cancer: 10 years of experience and development. Expert Rev Anticancer Ther. 2017;17(2):129–42.PubMedCrossRef
193.
Braconi C, Bracci R, Cellerino R. Molecular targets in Gastrointestinal Stromal Tumors (GIST) therapy. Curr Cancer Drug Targets. 2008;8(5):359–66.PubMedCrossRef
194.
Gomez-Saez JM. Sunitinib for the treatment of thyroid cancer. Expert Opin Investig Drugs. 2016;25(11):1345–52.PubMedCrossRef
195.
Young K, Iyer R, Morganstein D, Chau I, Cunningham D, Starling N. Pancreatic neuroendocrine tumors: a review. Future Oncol. 2015;11(5):853–64.PubMedCrossRef
196.
Abdel-Aziz AK, Abdel-Naim AB, Shouman S, Minucci S, Elgendy M. From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib. Front Pharmacol. 2017;8:718.PubMedPubMedCentralCrossRef
197.
Oslob JD, Romanowski MJ, Allen DA, Baskaran S, Bui M, Elling RA, Flanagan WM, Fung AD, Hanan EJ, Harris S, et al. Discovery of a potent and selective aurora kinase inhibitor. Bioorg Med Chem Lett. 2008;18(17):4880–4.PubMedCrossRef
198.
Arbitrario JP, Belmont BJ, Evanchik MJ, Flanagan WM, Fucini RV, Hansen SK, Harris SO, Hashash A, Hoch U, Hogan JN, et al. SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol. 2010;65(4):707–17.PubMedCrossRef
199.
Kim YS, Keyser SG, Schneekloth JS Jr. Synthesis of 2′,3′,4′-trihydroxyflavone (2-D08), an inhibitor of protein sumoylation. Bioorg Med Chem Lett. 2014;24(4):1094–7.PubMedPubMedCentralCrossRef
200.
Fujino N, Kubo H, Maciewicz RA. Phenotypic screening identifies Axl kinase as a negative regulator of an alveolar epithelial cell phenotype. Lab Invest. 2017;97(9):1047–62.PubMedCrossRef
201.
Zhang W, DeRyckere D, Hunter D, Liu J, Stashko MA, Minson KA, Cummings CT, Lee M, Glaros TG, Newton DL, et al. UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor. J Med Chem. 2014;57(16):7031–41.PubMedPubMedCentralCrossRef
202.
Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res. 2013;19(1):279–90.PubMedCrossRef
203.
Christoph S, Deryckere D, Schlegel J, Frazer JK, Batchelor LA, Trakhimets AY, Sather S, Hunter DM, Cummings CT, Liu J, et al. UNC569, a novel small-molecule mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo. Mol Cancer Ther. 2013;12(11):2367–77.PubMedCrossRef
204.
Liu J, Yang C, Simpson C, Deryckere D, Van Deusen A, Miley MJ, Kireev D, Norris-Drouin J, Sather S, Hunter D, et al. Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia. ACS Med Chem Lett. 2012;3(2):129–34.PubMedPubMedCentralCrossRef
205.
Torres KE, Zhu QS, Bill K, Lopez G, Ghadimi MP, Xie X, Young ED, Liu J, Nguyen T, Bolshakov S, et al. Activated MET is a molecular prognosticator and potential therapeutic target for malignant peripheral nerve sheath tumors. Clin Cancer Res. 2011;17(12):3943–55.PubMedPubMedCentralCrossRef
206.
Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308.PubMedCrossRef
207.
You WK, Sennino B, Williamson CW, Falcon B, Hashizume H, Yao LC, Aftab DT, McDonald DM. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 2011;71(14):4758–68.PubMedPubMedCentralCrossRef
208.
Viola D, Cappagli V, Elisei R. Cabozantinib (XL184) for the treatment of locally advanced or metastatic progressive medullary thyroid cancer. Future Oncol. 2013;9(8):1083–92.PubMedCrossRef
209.
Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639–46.PubMedPubMedCentralCrossRef
210.
Powles T, Motzer RJ, Escudier B, Pal S, Kollmannsberger C, Pikiel J, Gurney H, Rha SY, Park SH, Geertsen PF, et al. Outcomes based on prior therapy in the phase 3 METEOR trial of cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018;119(6):663–9.PubMedPubMedCentralCrossRef
211.
Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018;118(9):1176–8.PubMedPubMedCentralCrossRef
212.
Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917–27.PubMedCrossRef
213.
Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1814–23.PubMedPubMedCentralCrossRef
214.
Kelley RK, Verslype C, Cohn AL, Yang TS, Su WC, Burris H, Braiteh F, Vogelzang N, Spira A, Foster P, et al. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study. Ann Oncol. 2017;28(3):528–34.PubMedPubMedCentralCrossRef
215.
Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr, Blumenschein GR Jr, Krzakowski MJ, Robinet G, Godbert B, Barlesi F, et al. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2013;31(32):4105–14.PubMedPubMedCentralCrossRef
216.
Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018;379(1):54–63.PubMedCrossRefPubMedCentral
217.
Schoffski P, Gordon M, Smith DC, Kurzrock R, Daud A, Vogelzang NJ, Lee Y, Scheffold C, Shapiro GI. Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours. Eur J Cancer. 2017;86:296–304.PubMedCrossRef
218.
Tolaney SM, Nechushtan H, Ron IG, Schoffski P, Awada A, Yasenchak CA, Laird AD, O'Keeffe B, Shapiro GI, Winer EP. Cabozantinib for metastatic breast carcinoma: results of a phase II placebo-controlled randomized discontinuation study. Breast Cancer Res Treat. 2016;160(2):305–12.PubMedPubMedCentralCrossRef
219.
Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31(4):412–9.PubMedCrossRef
220.
Hellerstedt BA, Vogelzang NJ, Kluger HM, Yasenchak CA, Aftab DT, Ramies DA, Gordon MS, Lara P Jr. Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non-small-cell Lung Carcinoma. Clin Lung Cancer. 2019;20(2):74–81 e71.PubMedCrossRef
221.
222.
Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, et al. Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl )-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem. 2009;52(5):1251–4.PubMedCrossRef
223.
Sharma S, Zeng JY, Zhuang CM, Zhou YQ, Yao HP, Hu X, Zhang R, Wang MH. Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents. Mol Cancer Ther. 2013;12(5):725–36.PubMedCrossRef
224.
Kim KS, Zhang L, Schmidt R, Cai ZW, Wei D, Williams DK, Lombardo LJ, Trainor GL, Xie D, Zhang Y, et al. Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities. J Med Chem. 2008;51(17):5330–41.PubMedCrossRef
225.
Dai Y, Bae K, Pampo C, Siemann DW. Impact of the small molecule Met inhibitor BMS-777607 on the metastatic process in a rodent tumor model with constitutive c-Met activation. Clin Exp Metastasis. 2012;29(3):253–61.PubMedCrossRef
226.
Cheng CT, Chen YY, Wu RC, Tsai CY, Chiang KC, Yeh TS, Chen MH, Yeh CN. METRON dual inhibitor, BMS777607, suppresses cholangiocarcinoma cell growth, and METRON upregulation indicates worse prognosis for intrahepatic cholangiocarcinoma patients. Oncol Rep. 2018;40(3):1411–21.PubMed
227.
Nurhayati RW, Ojima Y, Taya M. BMS-777607 promotes megakaryocytic differentiation and induces polyploidization in the CHRF-288-11 cells. Hum Cell. 2015;28(2):65–72.PubMedCrossRef
228.
Yan SB, Um SL, Peek VL, Stephens JR, Zeng W, Konicek BW, Liu L, Manro JR, Wacheck V, Walgren RA. MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping. Invest New Drugs. 2018;36(4):536–44.PubMedCrossRef
229.
Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR, et al. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs. 2013;31(4):833–44.PubMedCrossRef
230.
Barat S, Bozko P, Chen X, Scholta T, Hanert F, Gotze J, Malek NP, Wilkens L, Plentz RR. Targeting c-MET by LY2801653 for treatment of cholangiocarcinoma. Mol Carcinog. 2016;55(12):2037–50.PubMedCrossRef
231.
Wu W, Bi C, Credille KM, Manro JR, Peek VL, Donoho GP, Yan L, Wijsman JA, Yan SB, Walgren RA. Inhibition of tumor growth and metastasis in non-small cell lung cancer by LY2801653, an inhibitor of several oncokinases, including MET. Clin Cancer Res. 2013;19(20):5699–710.PubMedCrossRef
232.
Kawada I, Hasina R, Arif Q, Mueller J, Smithberger E, Husain AN, Vokes EE, Salgia R. Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer. Cancer Res. 2014;74(3):884–95.PubMedCrossRef
233.
Qian F, Engst S, Yamaguchi K, Yu P, Won KA, Mock L, Lou T, Tan J, Li C, Tam D, et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 2009;69(20):8009–16.PubMedCrossRef
234.
Martinelli E, Martini G, Cardone C, Troiani T, Liguori G, Vitagliano D, Napolitano S, Morgillo F, Rinaldi B, Melillo RM, et al. AXL is an oncotarget in human colorectal cancer. Oncotarget. 2015;6(27):23281–96.PubMedPubMedCentralCrossRef
235.
Eder JP, Shapiro GI, Appleman LJ, Zhu AX, Miles D, Keer H, Cancilla B, Chu F, Hitchcock-Bryan S, Sherman L, et al. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin Cancer Res. 2010;16(13):3507–16.PubMedCrossRef
236.
Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, Rini BI, Srinivas S, Stein MN, Adams LM, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol. 2013;31(2):181–6.PubMedCrossRef
237.
Yau TCC, Lencioni R, Sukeepaisarnjaroen W, Chao Y, Yen CJ, Lausoontornsiri W, Chen PJ, Sanpajit T, Camp A, Cox DS, et al. A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma. Clin Cancer Res. 2017;23(10):2405–13.PubMedCrossRef
238.
Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget. 2016;7(4):4093–109.PubMedCrossRef
239.
240.
Bonfils C, Beaulieu N, Fournel M, Ste-Croix H, Besterman JM, Maroun CR. The combination of MGCD265, a Met/VEGFR inhibitor in clinical development, and erlotinib potently inhibits tumor growth by altering multiple pathways including glycolysis. Cancer Res. 2012;72. https://​doi.​org/​10.​1158/​1538-7445.​Am2012-1790.
241.
Do KT, Macconaill L, Dubuc A, Chen I, Chao R, Tassell V, Christensen J, Shapiro GI, Sholl LM. Evaluation of the MET/AXL Receptor Tyrosine Kinase (RTK) Inhibitor MGCD265 in a Patient with Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring AXL Amplification. J Thorac Oncol. 2015;10(9):S797.
242.
Linklater ES, Tovar EA, Essenburg CJ, Turner L, Madaj Z, Winn ME, Melnik MK, Korkaya H, Maroun CR, Christensen JG, et al. Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers. Oncotarget. 2016;7(43):69903–15.PubMedPubMedCentralCrossRef
243.
244.
Chan WW, Wise SC, Kaufman MD, Ahn YM, Ensinger CL, Haack T, Hood MM, Jones J, Lord JW, Lu WP, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011;19(4):556–68.PubMedPubMedCentralCrossRef
245.
Shen Y, Zhang W, Liu J, He J, Cao R, Chen X, Peng X, Xu H, Zhao Q, Zhong J, et al. Therapeutic activity of DCC-2036, a novel tyrosine kinase inhibitor, against triple-negative breast cancer patient-derived xenografts by targeting AXL/MET. Int J Cancer. 2019;144(3):651–64.PubMedCrossRef
246.
Rho JK, Choi YJ, Kim SY, Kim TW, Choi EK, Yoon SJ, Park BM, Park E, Bae JH, Choi CM, et al. MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation. Cancer Res. 2014;74(1):253–62.PubMedCrossRef
247.
Shin JS, Hong SW, Moon JH, Kim JS, Jung KA, Kim SM, Lee DH, Kim I, Yoon SJ, Lee CG, et al. NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants. Invest New Drugs. 2014;32(3):389–99.PubMedCrossRef
248.
Sawyers CL. Opportunities and challenges in the development of kinase inhibitor therapy for cancer. Genes Dev. 2003;17(24):2998–3010.PubMedCrossRef
249.
Leconet W, Larbouret C, Chardes T, Thomas G, Neiveyans M, Busson M, Jarlier M, Radosevic-Robin N, Pugniere M, Bernex F, et al. Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy. Oncogene. 2014;33(47):5405–14.PubMedCrossRef
250.
Liu R, Gong M, Li X, Zhou Y, Gao W, Tulpule A, Chaudhary PM, Jung J, Gill PS. Induction, regulation, and biologic function of Axl receptor tyrosine kinase in Kaposi sarcoma. Blood. 2010;116(2):297–305.PubMedPubMedCentralCrossRef
251.
Wang W, Zhao J, Wen X, Lin CC, Li J, Huang Q, Yu Y, Lin SY, Li C. MicroPET/CT Imaging of AXL Downregulation by HSP90 Inhibition in Triple-Negative Breast Cancer. Contrast Media Mol Imaging. 2017;2017:1686525.PubMedPubMedCentral
252.
Boshuizen J, Koopman LA, Krijgsman O, Shahrabi A, van den Heuvel EG, Ligtenberg MA, Vredevoogd DW, Kemper K, Kuilman T, Song JY, et al. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat Med. 2018;24(2):203–12.PubMedCrossRef
253.
Cho JH, Okuma A, Al-Rubaye D, Intisar E, Junghans RP, Wong WW. Engineering Axl specific CAR and SynNotch receptor for cancer therapy. Sci Rep. 2018;8(1):3846.PubMedPubMedCentralCrossRef
254.
Chames P, Van Regenmortel M, Weiss E, Baty D. Therapeutic antibodies: successes, limitations and hopes for the future. Br J Pharmacol. 2009;157(2):220–33.PubMedPubMedCentralCrossRef
255.
Cerchia L, Esposito CL, Camorani S, Rienzo A, Stasio L, Insabato L, Affuso A, de Franciscis V. Targeting Axl with an high-affinity inhibitory aptamer. Mol Ther. 2012;20(12):2291–303.PubMedPubMedCentralCrossRef
256.
Esposito CL, Catuogno S, de Franciscis V, Cerchia L. New insight into clinical development of nucleic acid aptamers. Discov Med. 2011;11(61):487–96.PubMed
257.
Russo V, Paciocco A, Affinito A, Roscigno G, Fiore D, Palma F, Galasso M, Volinia S, Fiorelli A, Esposito CL, et al. Aptamer-miR-34c Conjugate Affects Cell Proliferation of Non-Small-Cell Lung Cancer Cells. Mol Ther Nucleic Acids. 2018;13:334–46.PubMedPubMedCentralCrossRef
258.
O'Bryan JP, Fridell YW, Koski R, Varnum B, Liu ET. The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage. J Biol Chem. 1995;270(2):551–7.PubMedCrossRef
259.
Costa M, Bellosta P, Basilico C. Cleavage and release of a soluble form of the receptor tyrosine kinase ARK in vitro and in vivo. J Cell Physiol. 1996;168(3):737–44.PubMedCrossRef
260.
Kariolis MS, Miao YR, Jones DS 2nd, Kapur S, Mathews GAJ II, Cochran JR. An engineered Axl ‘decoy receptor’ effectively silences the Gas6-Axl signaling axis. Nat Chem Biol. 2014;10(11):977–83.PubMedPubMedCentralCrossRef
261.
Dengler M, Staufer K, Huber H, Stauber R, Bantel H, Weiss KH, Starlinger P, Pock H, Kloters-Plachky P, Gotthardt DN, et al. Soluble Axl is an accurate biomarker of cirrhosis and hepatocellular carcinoma development: results from a large scale multicenter analysis. Oncotarget. 2017;8(28):46234–48.PubMedPubMedCentralCrossRef
262.
263.
Paccez JD, Duncan K, Sekar D, Correa RG, Wang Y, Gu X, Bashin M, Chibale K, Libermann TA, Zerbini LF. Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl. Oncogenesis. 2019;8(3):14.PubMedPubMedCentralCrossRef
264.
Tan L, Zhang Z, Gao D, Chan S, Luo J, Tu ZC, Zhang ZM, Ding K, Ren X, Lu X. Quinolone antibiotic derivatives as new selective Axl kinase inhibitors. Eur J Med Chem. 2019;166:318–27.PubMedCrossRef
265.
Kim S, Kim KC, Lee C. Mistletoe (Viscum album) extract targets Axl to suppress cell proliferation and overcome cisplatin- and erlotinib-resistance in non-small cell lung cancer cells. Phytomedicine. 2017;36:183–93.PubMedCrossRef
Metadata
Title
AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications
Authors
Chenjing Zhu
Yuquan Wei
Xiawei Wei
Publication date
01-12-2019
Publisher
BioMed Central
Keywords
NSCLC
NSCLC
Published in
Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-019-1090-3

Other articles of this Issue 1/2019

Molecular Cancer 1/2019 Go to the issue

Research

Loss of the transcriptional repressor TGIF1 results in enhanced Kras-driven development of pancreatic cancer

Research

Activation of LncRNA TINCR by H3K27 acetylation promotes Trastuzumab resistance and epithelial-mesenchymal transition by targeting MicroRNA-125b in breast Cancer

Review

Exosomes promote pre-metastatic niche formation in ovarian cancer

Review

The novel roles of circRNAs in human cancer

Research

Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N6-methyladenosine of Notch1

Research

N6-methyladenosine induced miR-143-3p promotes the brain metastasis of lung cancer via regulation of VASH1
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits