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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2022

Open Access 01-12-2022 | NSCLC | Review

Emerging strategies to overcome resistance to third-generation EGFR inhibitors

Authors: Kunyu Shi, Guan Wang, Junping Pei, Jifa Zhang, Jiaxing Wang, Liang Ouyang, Yuxi Wang, Weimin Li

Published in: Journal of Hematology & Oncology | Issue 1/2022

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Abstract

Epidermal growth factor receptor (EGFR), the receptor for members of the epidermal growth factor family, regulates cell proliferation and signal transduction; moreover, EGFR is related to the inhibition of tumor cell proliferation, angiogenesis, invasion, metastasis, and apoptosis. Therefore, EGFR has become an important target for the treatment of cancer, including non-small cell lung cancer, head and neck cancer, breast cancer, glioma, cervical cancer, and bladder cancer. First- to third-generation EGFR inhibitors have shown considerable efficacy and have significantly improved disease prognosis. However, most patients develop drug resistance after treatment. The challenge of overcoming intrinsic and acquired resistance in primary and recurrent cancer mediated by EGFR mutations is thus driving the search for alternative strategies in the design of new therapeutic agents. In view of resistance to third-generation inhibitors, understanding the intricate mechanisms of resistance will offer insight for the development of more advanced targeted therapies. In this review, we discuss the molecular mechanisms of resistance to third-generation EGFR inhibitors and review recent strategies for overcoming resistance, new challenges, and future development directions.
Literature
1.
2.
da Cunha SG, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49–69.CrossRef
3.
Campbell ID, Bork P. Epidermal growth factor-like modules. Curr Opin Struct Biol. 1993;3:385–92.CrossRef
4.
Roskoski R. The ERBB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 2014;79:34–74.PubMedCrossRef
5.
Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28(Suppl 1):S24–31.PubMedPubMedCentralCrossRef
6.
Herbst RS, Langer CJ. Epidermal growth factor receptors as a target for cancer treatment: the emerging role of IMC-C225 in the treatment of lung and head and neck cancers. Semin Oncol. 2002;29:27–36.PubMedCrossRef
7.
Normanno N, Bianco C, De Luca A, Salomon DS. The role of EGF-related peptides in tumor growth. Front Biosci. 2001;6:D685–707.PubMedCrossRef
8.
9.
Sabbah DA, Hajjo R, Sweidan K. Review on epidermal growth factor receptor (EGFR) structure, signaling pathways, interactions, and recent updates of EGFR inhibitors. Curr Top Med Chem. 2020;20:815–34.PubMedCrossRef
10.
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046–61.PubMedPubMedCentralCrossRef
11.
Ricordel C, Friboulet L, Facchinetti F, Soria JC. Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer. Ann Oncol. 2018;29:i28–37.PubMedCrossRef
12.
Roskoski R Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res. 2016;103:26–48.PubMedCrossRef
13.
Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase iii study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–34.PubMedCrossRef
14.
Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213–22.PubMedCrossRef
15.
Zhang H. Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer. Drug Des Devel Ther. 2016;10:3867–72.PubMedPubMedCentralCrossRef
16.
17.
Jiang T, Zhou C. Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor-resistant non-small cell lung cancer. Transl Lung Cancer Res. 2014;3:370–2.PubMedPubMedCentral
18.
Yan XE, Zhu SJ, Liang L, Zhao P, Choi HG, Yun CH. Structural basis of mutant-selectivity and drug-resistance related to CO-1686. Oncotarget. 2017;8:53508–17.PubMedPubMedCentralCrossRef
19.
Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725–37.PubMedPubMedCentralCrossRef
20.
Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med. 2016;22:262–9.PubMedPubMedCentralCrossRef
21.
Guibert N, Barlesi F, Descourt R, Lena H, Besse B, Beau-Faller M, et al. Characteristics and outcomes of patients with lung cancer harboring multiple molecular alterations: results from the IFCT study biomarkers france. J Thorac Oncol. 2017;12:963–73.PubMedCrossRef
22.
Li X, Wang S, Li B, Wang Z, Shang S, Shao Y, et al. Bim deletion polymorphism confers resistance to osimertinib in EGFR T790M lung cancer: a case report and literature review. Target Oncol. 2018;13:517–23.PubMedCrossRef
23.
Eck MJ, Yun CH. Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta. 2010;1804:559–66.PubMedCrossRef
24.
Westover D, Zugazagoitia J, Cho BC, Lovly CM, Paz-Ares L. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol. 2018;29:i10–9.PubMedPubMedCentralCrossRef
25.
Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009;462:1070–4.PubMedPubMedCentralCrossRef
26.
Zhang Q, Zhang XC, Yang JJ, Yang ZF, Bai Y, Su J, et al. EGFR L792H and G796R: two novel mutations mediating resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib. J Thorac Oncol. 2018;13:1415–21.PubMedCrossRef
27.
28.
Ou SI, Cui J, Schrock AB, Goldberg ME, Zhu VW, Albacker L, et al. Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib. Lung Cancer. 2017;108:228–31.PubMedCrossRef
29.
Castellano GM, Aisner J, Burley SK, Vallat B, Yu HA, Pine SR, et al. A novel acquired exon 20 EGFR M766Q mutation in lung adenocarcinoma mediates osimertinib resistance but is sensitive to neratinib and poziotinib. J Thorac Oncol. 2019;14:1982–8.PubMedPubMedCentralCrossRef
30.
Liu J, Jin B, Su H, Qu X, Liu Y. Afatinib helped overcome subsequent resistance to osimertinib in a patient with NSCLC having leptomeningeal metastasis baring acquired EGFR L718Q mutation: a case report. BMC Cancer. 2019;19:702.PubMedPubMedCentralCrossRef
31.
Bersanelli M, Minari R, Bordi P, Gnetti L, Bozzetti C, Squadrilli A, et al. L718Q mutation as new mechanism of acquired resistance to AZD9291 in EGFR -mutated NSCLC. J Thorac Oncol. 2016;11:e121–3.PubMedCrossRef
32.
Callegari D, Ranaghan KE, Woods CJ, Minari R, Tiseo M, Mor M, et al. L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib. Chem Sci. 2018;9:2740–9.PubMedPubMedCentralCrossRef
33.
Yang Z, Yang J, Chen Y, Shao YW, Wang X. Acquired EGFR L718V mutation as the mechanism for osimertinib resistance in a T790M-negative non-small-cell lung cancer patient. Target Oncol. 2019;14:369–74.PubMedCrossRef
34.
Fassunke J, Muller F, Keul M, Michels S, Dammert MA, Schmitt A, et al. Overcoming EGFR (G724S)-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nat Commun. 2018;9:4655.PubMedPubMedCentralCrossRef
35.
Tu HY, Ke EE, Yang JJ, Sun YL, Yan HH, Zheng MY, et al. A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer. Lung Cancer. 2017;114:96–102.PubMedCrossRef
36.
Xu J, Jin B, Chu T, Dong X, Yang H, Zhang Y, et al. EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: a real-world study in china. Lung Cancer. 2016;96:87–92.PubMedCrossRef
37.
Shen YC, Tseng GC, Tu CY, Chen WC, Liao WC, Chen WC, et al. Comparing the effects of afatinib with gefitinib or erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations. Lung Cancer. 2017;110:56–62.PubMedCrossRef
38.
Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ, et al. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin Cancer Res. 2015;21:3913–23.PubMedPubMedCentralCrossRef
39.
Piotrowska Z, Isozaki H, Lennerz JK, Gainor JF, Lennes IT, Zhu VW, et al. Landscape of acquired resistance to osimertinib in EGFR -mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov. 2018;8:1529–39.PubMedPubMedCentralCrossRef
40.
Piotrowska Z, Niederst MJ, Karlovich CA, Wakelee HA, Neal JW, Mino-Kenudson M, et al. Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov. 2015;5:713–22.PubMedPubMedCentralCrossRef
41.
Nukaga S, Yasuda H, Tsuchihara K, Hamamoto J, Masuzawa K, Kawada I, et al. Amplification of EGFR wild-type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. Cancer Res. 2017;77:2078–89.PubMedCrossRef
42.
Huang C, Zou Q, Liu H, Qiu B, Li Q, Lin Y, et al. Management of non-small cell lung cancer patients with MET exon 14 skipping mutations. Curr Treat Opt Oncol. 2020;21:33.CrossRef
43.
Mueller KL, Madden JM, Zoratti GL, Kuperwasser C, List K, Boerner JL. Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of MET. Breast Cancer Res. 2012;14:R104.PubMedPubMedCentralCrossRef
44.
Hsu CC, Liao BC, Liao WY, Markovets A, Stetson D, Thress K, et al. Exon 16-skipping HER2 as a novel mechanism of osimertinib resistance in EGFR L858R/T790M-positive non-small cell lung cancer. J Thorac Oncol. 2020;15:50–61.PubMedCrossRef
45.
Ou S-HI, Madison R, Robichaux JP, Ross JS, Miller VA, Ali SM, et al. Characterization of 648 non-small cell lung cancer (NSCLC) cases with 28 unique HER2 exon 20 insertions. J Clin Oncol. 2019;37:9063–63.CrossRef
46.
Gao G, Li X, Wang Q, Zhang Y, Chen J, Shu Y, et al. Single-arm, phase ii study of pyrotinib in advanced non-small cell lung cancer (NSCLC) patients with HER2 exon 20 mutation. J Clin Oncol. 2019;37:9089–189.CrossRef
47.
48.
Zhu J, Yang Q, Xu W. Iterative upgrading of small molecular tyrosine kinase inhibitors for EGFR mutation in NSCLC: necessity and perspective. Pharmaceutics. 2021;13:1500.PubMedPubMedCentralCrossRef
49.
Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A, et al. AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells. Nat Commun. 2019;10:259.PubMedPubMedCentralCrossRef
50.
Yano S, Yamada T, Takeuchi S, Tachibana K, Minami Y, Yatabe Y, et al. Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort. J Thorac Oncol. 2011;6:2011–7.PubMedCrossRef
51.
Kim TM, Song A, Kim DW, Kim S, Ahn YO, Keam B, et al. Mechanisms of acquired resistance to AZD9291 a mutation-selective, irreversible EGFR inhibitor. J Thorac Oncol. 2015;10:1736–44.PubMedCrossRef
52.
Papadimitrakopoulou VA, Wu YL, Han JY, Ahn MJ, Ramalingam SS, John T, et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Ann Oncol. 2018;29:741–841.CrossRef
53.
Tanaka H, Sakagami H, Kaneko N, Konagai S, Yamamoto H, Matsuya T, et al. Mutant-selective irreversible EGFR inhibitor, naquotinib, inhibits tumor growth in NSCLC models with EGFR-activating mutations, T790M mutation, and AXL overexpression. Mol Cancer Ther. 2019;18:1366–73.PubMedCrossRef
54.
Park JH, Choi YJ, Kim SY, Lee JE, Sung KJ, Park S, et al. Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer. Oncotarget. 2016;7:22005–15.PubMedPubMedCentralCrossRef
55.
Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol. 2003;4:842–54.PubMedCrossRef
56.
Cheetham GMT, Knegtel RMA, Coll JT, Renwick SB, Swenson L, Weber P, et al. Crystal structure of aurora-2, an oncogenic serine/threonine kinase*. J Biol Chem. 2002;277:42419–22.PubMedCrossRef
57.
Pradhan T, Gupta O, Singh G, Monga V. Aurora kinase inhibitors as potential anticancer agents: recent advances. Eur J Med Chem. 2021;221:113495.PubMedCrossRef
58.
Falchook GS, Bastida CC, Kurzrock R. Aurora kinase inhibitors in oncology clinical trials: current state of the progress. Semin Oncol. 2015;42:832–48.PubMedCrossRef
59.
Hu L, Fan M, Shi S, Song X, Wang F, He H, et al. Dual target inhibitors based on EGFR: promising anticancer agents for the treatment of cancers (2017-). Eur J Med Chem. 2022;227:113963.PubMedCrossRef
60.
Tanaka K, Yu HA, Yang S, Han S, Selcuklu SD, Kim K, et al. Targeting aurora b kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer Cell. 2021;39(1245–61):e6.
61.
Mao C, Qiu LX, Liao RY, Du FB, Ding H, Yang WC, et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer. 2010;69:272–8.PubMedCrossRef
62.
Sunaga N, Shames DS, Girard L, Peyton M, Larsen JE, Imai H, et al. Knockdown of oncogenic KRAS in non-small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy. Mol Cancer Ther. 2011;10:336–46.PubMedPubMedCentralCrossRef
63.
Leonetti A, Facchinetti F, Rossi G, Minari R, Conti A, Friboulet L, et al. Braf in non-small cell lung cancer (NSCLC): pickaxing another brick in the wall. Cancer Treat Rev. 2018;66:82–94.PubMedCrossRef
64.
Ho CC, Liao WY, Lin CA, Shih JY, Yu CJ, Yang JC. Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J Thorac Oncol. 2017;12:567–72.PubMedCrossRef
65.
Ramalingam SS, Cheng Y, Zhou C, Ohe Y, Imamura F, Cho BC, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase iii flaura study. Ann Oncol. 2018;29:viii740.CrossRef
66.
Zhao M, Gao FH, Wang JY, Liu F, Yuan HH, Zhang WY, et al. JAK2/STAT3 signaling pathway activation mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-small-cell lung cancer. Lung Cancer. 2011;73:366–74.PubMedCrossRef
67.
Chaib I, Karachaliou N, Pilotto S, Codony Servat J, Cai X, Li X, et al. Co-activation of STAT3 and YES-associated protein 1 (YAP1) pathway in EGFR-mutant NSCLC. J Natl Cancer Inst. 2017;109.
68.
Soria J-C, Lee H-Y, Lee JI, Wang L, Issa J-P, Kemp BL, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res. 2002;8:1178–84.PubMed
69.
Zhang T, Qu R, Chan S, Lai M, Tong L, Feng F, et al. Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance. Mol Cancer. 2020;19:90.PubMedPubMedCentralCrossRef
70.
Zhu L, Chen Z, Zang H, Fan S, Gu J, Zhang G, et al. Targeting c-Myc to overcome acquired resistance of EGFR mutant NSCLC cells to the third-generation EGFR tyrosine kinase inhibitor, osimertinib. Cancer Res. 2021;81:4822–34.PubMedPubMedCentralCrossRef
71.
Weng CH, Chen LY, Lin YC, Shih JY, Lin YC, Tseng RY, et al. Epithelial–mesenchymal transition (emtEMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI. Oncogene. 2019;38:455–68.PubMedCrossRef
72.
73.
Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, et al. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol. 2008;28:6773–84.PubMedPubMedCentralCrossRef
74.
Liu CH, Huang Q, Jin ZY, Zhu CL, Liu Z, Wang C. miR-21 and KLF4 jointly augment epithelialmesenchymal transition via the Akt/ERK1/2 pathway. Int J Oncol. 2017;50:1109–15.PubMedPubMedCentralCrossRef
75.
Han Z, Zhou X, Li S, Qin Y, Chen Y, Liu H. Inhibition of miR-23a increases the sensitivity of lung cancer stem cells to erlotinib through PTEN/PI3K/Akt pathway. Oncol Rep. 2017;38:3064–70.PubMedCrossRef
76.
Shen H, Zhu F, Liu J, Xu T, Pei D, Wang R, et al. Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer. PLoS ONE. 2014;9:e103305.PubMedPubMedCentralCrossRef
77.
78.
Del Re M, Arrigoni E, Restante G, Passaro A, Rofi E, Crucitta S, et al. Concise review: resistance to tyrosine kinase inhibitors in non-small cell lung cancer: the role of cancer stem cells. Stem Cells. 2018;36:633–40.PubMedCrossRef
79.
Papadimitrakopoulou VA, Wu YL, Han JY, Ahn MJ, Ramalingam SS, John T, et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Ann Oncol. 2018;29:viii741.CrossRef
80.
Dorantes-Heredia R, Ruiz-Morales JM, Cano-Garcia F. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors. Transl Lung Cancer Res. 2016;5:401–12.PubMedPubMedCentralCrossRef
81.
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.PubMedPubMedCentralCrossRef
82.
Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol. 2015;16:e165-172.PubMedPubMedCentralCrossRef
83.
Norkowski E, Ghigna MR, Lacroix L, Le Chevalier T, Fadel E, Dartevelle P, et al. Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol. 2013;8:1265–71.PubMedCrossRef
84.
85.
Schoenfeld AJ, Chan JM, Kubota D, Sato H, Rizvi H, Daneshbod Y, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer. Clin Cancer Res. 2020;26:2654–63.PubMedPubMedCentralCrossRef
86.
Garassino MC, Cho BC, Kim JH, Mazieres J, Vansteenkiste J, Lena H, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol. 2018;19:521–36.PubMedPubMedCentralCrossRef
87.
Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res. 2016;22:4585–93.PubMedPubMedCentralCrossRef
88.
Haratani K, Hayashi H, Tanaka T, Kaneda H, Togashi Y, Sakai K, et al. Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment. Ann Oncol. 2017;28:1532–9.PubMedCrossRef
89.
Zheng Y, Hao S, Xiang C, Han Y, Shang Y, Zhen Q, et al. The correlation between SPP1 and immune escape of EGFR mutant lung adenocarcinoma was explored by bioinformatics analysis. Front Oncol. 2021;11:592854.PubMedPubMedCentralCrossRef
90.
Peng S, Wang R, Zhang X, Ma Y, Zhong L, Li K, et al. EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression. Mol Cancer. 2019;18:165.PubMedPubMedCentralCrossRef
91.
Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ, Arcila ME, et al. Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol. 2015;1:982–4.PubMedPubMedCentralCrossRef
92.
Wang Z, Yang JJ, Huang J, Ye JY, Zhang XC, Tu HY, et al. Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of first- and third-generation EGFR TKIs and shifts allelic configuration at resistance. J Thorac Oncol. 2017;12:1723–7.PubMedCrossRef
93.
Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, Piotrowska Z, et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res. 2015;21:3924–33.PubMedPubMedCentralCrossRef
94.
95.
Engel J, Richters A, Getlik M, Tomassi S, Keul M, Termathe M, et al. Targeting drug resistance in EGFR with covalent inhibitors: a structure-based design approach. J Med Chem. 2015;58:6844–63.PubMedCrossRef
96.
Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016;534:129–32.PubMedPubMedCentralCrossRef
97.
Lee S, Kim J, Duggirala KB, Go A, Shin I, Cho BC, et al. Allosteric inhibitor TREA-0236 containing non-hydrolysable quinazoline-4-one for EGFR T790M/C797S mutants inhibition. Bull Korean Chem Soc. 2018;39:895–8.CrossRef
98.
To C, Jang J, Chen T, Park E, Mushajiang M, De Clercq DJH, et al. Single and dual targeting of mutant EGFR with an allosteric inhibitor. Cancer Discov. 2019;9:926–43.PubMedPubMedCentralCrossRef
99.
Maity S, Pai KSR, Nayak Y. Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance. Pharmacol Rep. 2020;72:799–813.PubMedPubMedCentralCrossRef
100.
De Clercq DJH, Heppner DE, To C, Jang J, Park E, Yun C-H, et al. Discovery and optimization of dibenzodiazepinones as allosteric mutant-selective EGFR inhibitors. ACS Med Chem Lett. 2019;10:1549–53.PubMedPubMedCentralCrossRef
101.
Duplessis M, Goergler A, Jaeschke G, Kocer B, Kuhn B, Lazarski K, et al. COMPOUNDS. Publication number: 20210079005, March 18, 2021.
102.
Lu X, Zhang T, Zhu SJ, Xun Q, Tong L, Hu X, et al. Discovery of JND3229 as a new EGFR(C797S) mutant inhibitor with in vivo monodrug efficacy. ACS Med Chem Lett. 2018;9:1123–7.PubMedPubMedCentralCrossRef
103.
Engel J, Becker C, Lategahn J, Keul M, Ketzer J, Muhlenberg T, et al. Insight into the inhibition of drug-resistant mutants of the receptor tyrosine kinase EGFR. Angew Chem Int Ed Engl. 2016;55:10909–12.PubMedCrossRef
104.
Gunther M, Lategahn J, Juchum M, Doring E, Keul M, Engel J, et al. Trisubstituted pyridinylimidazoles as potent inhibitors of the clinically resistant L858R/T790M/C797S EGFR mutant: targeting of both hydrophobic regions and the phosphate binding site. J Med Chem. 2017;60:5613–37.PubMedCrossRef
105.
Park H, Jung HY, Mah S, Hong S. Discovery of EGF receptor inhibitors that are selective for the D746–750/T790M/C797S mutant through structure-based de novo design. Angew Chem Int Ed Engl. 2017;56:7634–8.PubMedCrossRef
106.
Zhang M, Wang Y, Wang J, Liu Z, Shi J, Li M, et al. Design, synthesis and biological evaluation of the quinazoline derivatives as L858R/T790M/C797S triple mutant epidermal growth factor receptor tyrosine kinase inhibitors. Chem Pharm Bull (Tokyo). 2020;68:971–80.CrossRef
107.
Shen J, Zhang T, Zhu SJ, Sun M, Tong L, Lai M, et al. Structure-based design of 5-methylpyrimidopyridone derivatives as new wild-type sparing inhibitors of the epidermal growth factor receptor triple mutant (EGFR(L858R/T790M/C797S). J Med Chem. 2019;62:7302–8.PubMedCrossRef
108.
Zhang H, Wang J, Shen Y, Wang HY, Duan WM, Zhao HY, et al. Discovery of 2,4,6-trisubstitued pyrido[3,4-d]pyrimidine derivatives as new EGFR-TKIs. Eur J Med Chem. 2018;148:221–37.PubMedCrossRef
109.
Hei YY, Shen Y, Wang J, Zhang H, Zhao HY, Xin M, et al. Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors. Bioorg Med Chem. 2018;26:2173–85.PubMedCrossRef
110.
Lei H, Fan S, Zhang H, Liu YJ, Hei YY, Zhang JJ, et al. Discovery of novel 9-heterocyclyl substituted 9H-purines as L858R/T790M/C797S mutant EGFR tyrosine kinase inhibitors. Eur J Med Chem. 2020;186:111888.PubMedCrossRef
111.
Lategahn J, Keul M, Klovekorn P, Tumbrink HL, Niggenaber J, Muller MP, et al. Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S. Chem Sci. 2019;10:10789–801.PubMedPubMedCentralCrossRef
112.
Hu X, Xun Q, Zhang T, Zhu S-J, Li Q, Tong L, et al. 2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant. Chin Chem Lett. 2020;31:1281–7.CrossRef
113.
Su Z, Yang T, Wang J, Lai M, Tong L, Wumaier G, et al. Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation. Bioorg Med Chem Lett. 2020;30:127327.PubMedCrossRef
114.
Lee Kwangho, SHIN Inji, CHOI Gildon, CHAE Chong Hak, Choe Hyeon Jeong, JUNG Myoung Eun, et al. N2,N4-diphenylpyrimidine-2,4-diamine derivative, method for preparing same, and pharmaceutical composition containing same as active ingredient for prevention or treatment of cancer. WO2018230934, 2018.
115.
Wu L, Liu X, Ding CZ, Chen S, Hu L, Zhao L, et al. Spiro-aryl-phosphorus-oxygen compound as fourth generation of EGFR kinase inhibitor. WO 2018108064 A1, 2016.
116.
Iwao M, Fukuda T, Ishibashi F, Uehara Y, Nishiya N, Oku Y, et al. Fourth-generation EGFR tyrosine kinase inhibitor. CN 110461850 A, 2019.
117.
Boese D, Dahmann G, Engelhardt H, Petronczki M, Scharn D. New benzimidazole compounds and derivatives as EGFR inhibitors. WO 2019162323 A1, 2019.
118.
Ding K, Ding J, Shen J, Geng M, Lu X, Xie H, et al. Pyrimidopyridone or pyridopyridone compound and use thereof. WO 2019015593 A1, 2019.
119.
Ferlenghi F, Scalvini L, Vacondio F, Castelli R, Bozza N, Marseglia G, et al. A sulfonyl fluoride derivative inhibits EGFR(L858R/T790M/C797S) by covalent modification of the catalytic lysine. Eur J Med Chem. 2021;225:113786.PubMedCrossRef
120.
Morabito A, Piccirillo MC, Falasconi F, De Feo G, Del Giudice A, Bryce J, et al. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (vEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: Current status and future directions. Oncologist. 2009;14:378–90.PubMedCrossRef
121.
Li Q, Zhang T, Li S, Tong L, Li J, Su Z, et al. Discovery of potent and noncovalent reversible EGFR kinase inhibitors of EGFR(L858R/T790M/C797S). ACS Med Chem Lett. 2019;10:869–73.PubMedPubMedCentralCrossRef
122.
Wittlinger F, Heppner DE, To C, Gunther M, Shin BH, Rana JK, et al. Design of a “two-in-one” mutant-selective epidermal growth factor receptor inhibitor that spans the orthosteric and allosteric sites. J Med Chem. 2022;65:1370–83.PubMedCrossRef
123.
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–7.PubMedPubMedCentralCrossRef
124.
Noble ME, Endicott JA, Johnson LN. Protein kinase inhibitors: Insights into drug design from structure. Science. 2004;303:1800–5.PubMedCrossRef
125.
Bondeson DP, Mares A, Smith IE, Ko E, Campos S, Miah AH, et al. Catalytic in vivo protein knockdown by small-molecule protacs. Nat Chem Biol. 2015;11:611–7.PubMedPubMedCentralCrossRef
126.
Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al. Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348:1376–81.PubMedPubMedCentralCrossRef
127.
Scheepstra M, Hekking KFW, van Hijfte L, Folmer RHA. Bivalent ligands for protein degradation in drug discovery. Comput Struct Biotechnol J. 2019;17:160–76.PubMedPubMedCentralCrossRef
128.
129.
Chamberlain PP, Hamann LG. Development of targeted protein degradation therapeutics. Nat Chem Biol. 2019;15:937–44.PubMedCrossRef
130.
Churcher I. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones? J Med Chem. 2018;61:444–52.PubMedCrossRef
131.
132.
Toure M, Crews CM. Small-molecule protacs: new approaches to protein degradation. Angew Chem Int Ed Engl. 2016;55:1966–73.PubMedCrossRef
133.
Jang J, To C, De Clercq DJH, Park E, Ponthier CM, Shin BH, et al. Mutant-selective allosteric EGFR degraders are effective against a broad range of drug-resistant mutations. Angew Chem Int Ed Engl. 2020;59:14481–9.PubMedPubMedCentralCrossRef
134.
Zhao HY, Yang XY, Lei H, Xi XX, Lu SM, Zhang JJ, et al. Discovery of potent small molecule protacs targeting mutant EGFR. Eur J Med Chem. 2020;208:112781.PubMedCrossRef
135.
Qu X, Liu H, Song X, Sun N, Zhong H, Qiu X, et al. Effective degradation of EGFRL858R+T790M mutant proteins by CRBN-based PROTAC s through both proteosome and autophagy/lysosome degradation systems. Eur J Med Chem. 2021;218:113328.PubMedCrossRef
136.
Zheng M, Huo J, Gu X, Wang Y, Wu C, Zhang Q, et al. Rational design and synthesis of novel dual PROTACS for simultaneous degradation of EGFR and PARP. J Med Chem. 2021;64:7839–52.PubMedCrossRef
137.
Kim JH, Nam B, Choi YJ, Kim SY, Lee JE, Sung KJ, et al. Enhanced glycolysis supports cell survival in EGFR-mutant lung adenocarcinoma by inhibiting autophagy-mediated EGFR degradation. Cancer Res. 2018;78:4482–96.PubMedCrossRef
138.
139.
Takahashi D, Moriyama J, Nakamura T, Miki E, Takahashi E, Sato A, et al. Autacs: Cargo-specific degraders using selective autophagy. Mol Cell. 2019;76(797–810):e10.
140.
Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382:41–50.PubMedCrossRef
141.
142.
He K, Xu J, Liang J, Jiang J, Tang M, Ye X, et al. Discovery of a novel EGFR-targeting antibody-drug conjugate, SHR-A1307, for the treatment of solid tumors resistant or refractory to anti-EGFR therapies. Mol Cancer Ther. 2019;18:1104–14.PubMedCrossRef
143.
Xu R-h, Qiu M-Z, Zhang Y, Wei X-L, Hu C. First-in-human dose-escalation study of anti-EGFR adc MRG003 in patients with relapsed/refractory solid tumors. J Clin Oncol. 2020;38:3550–50.CrossRef
144.
Li Z, Wang M, Yao X, Luo W, Qu Y, Yu D, et al. Development of a novel EGFR-targeting antibody-drug conjugate for pancreatic cancer therapy. Target Oncol. 2019;14:93–105.PubMedCrossRef
145.
Shi P, Oh YT, Zhang G, Yao W, Yue P, Li Y, et al. Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment. Cancer Lett. 2016;380:494–504.PubMedCrossRef
146.
Giroux-Leprieur E, Dumenil C, Chinet T. Combination of crizotinib and osimertinib or erlotinib might overcome MET-mediated resistance to EGFR tyrosine kinase inhibitor in EGFR-mutated adenocarcinoma. J Thorac Oncol. 2018;13:e232–4.PubMedCrossRef
147.
Kang J, Chen HJ, Wang Z, Liu J, Li B, Zhang T, et al. Osimertinib and cabozantinib combinatorial therapy in an EGFR-mutant lung adenocarcinoma patient with multiple MET secondary-site mutations after resistance to crizotinib. J Thorac Oncol. 2018;13:e49–53.PubMedCrossRef
148.
Fujino T, Suda K, Mitsudomi T. Emerging MET tyrosine kinase inhibitors for the treatment of non-small cell lung cancer. Expert Opin Emerg Drugs. 2020;25:229–49.PubMedCrossRef
149.
Quintanal-Villalonga A, Molina-Pinelo S, Cirauqui C, Ojeda-Marquez L, Marrugal A, Suarez R, et al. FGFR1 cooperates with EGFR in lung cancer oncogenesis, and their combined inhibition shows improved efficacy. J Thorac Oncol. 2019;14:641–55.PubMedCrossRef
150.
Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18:1590–9.PubMedPubMedCentralCrossRef
151.
Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun. 2017;8:14768.PubMedPubMedCentralCrossRef
152.
Liu S, Li S, Hai J, Wang X, Chen T, Quinn MM, et al. Targeting HER2 aberrations in non-small cell lung cancer with osimertinib. Clin Cancer Res. 2018;24:2594–604.PubMedPubMedCentralCrossRef
153.
La Monica S, Cretella D, Bonelli M, Fumarola C, Cavazzoni A, Digiacomo G, et al. Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines. J Exp Clin Cancer Res. 2017;36:174.PubMedPubMedCentralCrossRef
154.
Jani JP, Arcari J, Bernardo V, Bhattacharya SK, Briere D, Cohen BD, et al. PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. Mol Cancer Ther. 2010;9:883–94.PubMedCrossRef
155.
Kim C, Giaccone G. MEK inhibitors under development for treatment of non-small-cell lung cancer. Expert Opin Investig Drugs. 2018;27:17–30.PubMedCrossRef
156.
Ortiz-Cuaran S, Scheffler M, Plenker D, Dahmen L, Scheel AH, Fernandez-Cuesta L, et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin Cancer Res. 2016;22:4837–47.PubMedCrossRef
157.
Della Corte CM, Ciaramella V, Cardone C, La Monica S, Alfieri R, Petronini PG, et al. Antitumor efficacy of dual blockade of EGFR signaling by osimertinib in combination with selumetinib or cetuximab in activated EGFR human NCLC tumor models. J Thorac Oncol. 2018;13:810–20.PubMedCrossRef
158.
Jacobsen K, Bertran-Alamillo J, Molina MA, Teixido C, Karachaliou N, Pedersen MH, et al. Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer. Nat Commun. 2017;8:410.PubMedPubMedCentralCrossRef
159.
Namba K, Shien K, Takahashi Y, Torigoe H, Sato H, Yoshioka T, et al. Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells. Mol Cancer Res. 2019;17:499–507.PubMedCrossRef
160.
Jimbo T, Hatanaka M, Komatsu T, Taira T, Kumazawa K, Maeda N, et al. DS-1205b, a novel selective inhibitor of AXL kinase, blocks resistance to EGFR-tyrosine kinase inhibitors in a non-small cell lung cancer xenograft model. Oncotarget. 2019;10:5152–67.PubMedPubMedCentralCrossRef
161.
Kim D, Bach DH, Fan YH, Luu TT, Hong JY, Park HJ, et al. AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells. Cell Death Dis. 2019;10:361.PubMedPubMedCentralCrossRef
162.
Liu YN, Tsai MF, Wu SG, Chang TH, Tsai TH, Gow CH, et al. Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer. Int J Cancer. 2019;145:1609–24.PubMedCrossRef
163.
Gu J, Qian L, Zhang G, Mahajan NP, Owonikoko TK, Ramalingam SS, et al. Inhibition of ACK1 delays and overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib. Lung Cancer. 2020;150:26–35.PubMedCrossRef
164.
Lawrence HR, Mahajan K, Luo Y, Zhang D, Tindall N, Huseyin M, et al. Development of novel ACK1/TNK2 inhibitors using a fragment-based approach. J Med Chem. 2015;58:2746–63.PubMedPubMedCentralCrossRef
165.
Sequist LV, Lynch TJ. EGFR tyrosine kinase inhibitors in lung cancer: an evolving story. Annu Rev Med. 2008;59:429–42.PubMedCrossRef
166.
Kummar S, Chen HX, Wright J, Holbeck S, Millin MD, Tomaszewski J, et al. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Nat Rev Drug Discov. 2010;9:843–56.PubMedCrossRef
167.
Anighoro A, Bajorath J, Rastelli G. Polypharmacology: challenges and opportunities in drug discovery. J Med Chem. 2014;57:7874–87.PubMedCrossRef
168.
Chen G, Bao Y, Weng Q, Zhao Y, Lu X, Fu L, et al. Compound 15c, a novel dual inhibitor of EGFR(L858R/T790M) and FGFR1, efficiently overcomes epidermal growth factor receptor-tyrosine kinase inhibitor resistance of non-small-cell lung cancers. Front Pharmacol. 2019;10:1533.PubMedCrossRef
169.
Cui Z, Chen S, Wang Y, Gao C, Chen Y, Tan C, et al. Design, synthesis and evaluation of azaacridine derivatives as dual-target EGFR and Src kinase inhibitors for antitumor treatment. Eur J Med Chem. 2017;136:372–81.PubMedCrossRef
170.
Mansour TS, Pallepati RR, Basetti V. Potent dual EGFR/HER4 tyrosine kinase inhibitors containing novel (1,2-dithiolan-4-yl)acetamides. Bioorg Med Chem Lett. 2020;30:127288.PubMedCrossRef
171.
El-Sayed NA, Nour MS, Salem MA, Arafa RK. New oxadiazoles with selective- COX-2 and EGFR dual inhibitory activity: design, synthesis, cytotoxicity evaluation and in silico studies. Eur J Med Chem. 2019;183:111693.PubMedCrossRef
172.
Abdelatef SA, El-Saadi MT, Amin NH, Abdelazeem AH, Omar HA, Abdellatif KRA. Design, synthesis and anticancer evaluation of novel spirobenzo[h]chromene and spirochromane derivatives with dual EGFR and B-RAF inhibitory activities. Eur J Med Chem. 2018;150:567–78.PubMedCrossRef
173.
174.
Chen Y, Wu J, Wang A, Qi Z, Jiang T, Chen C, et al. Discovery of n-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-met hoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (chmfl-alk/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC. Eur J Med Chem. 2017;139:674–97.PubMedCrossRef
175.
Jing T, Miao X, Jiang F, Guo M, Xing L, Zhang J, et al. Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors. Bioorg Med Chem. 2018;26:1784–96.PubMedCrossRef
176.
Kurup S, McAllister B, Liskova P, Mistry T, Fanizza A, Stanford D, et al. Design, synthesis and biological activity of n(4)-phenylsubstituted-7h-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase a and epidermal growth factor receptor kinase. J Enzyme Inhib Med Chem. 2018;33:74–84.PubMedCrossRef
177.
Gadekar PK, Urunkar G, Roychowdhury A, Sharma R, Bose J, Khanna S, et al. Design, synthesis and biological evaluation of 2,3-dihydroimidazo[2,1-b]thiazoles as dual EGFR and IGF1R inhibitors. Bioorg Chem. 2021;115:105151.PubMedCrossRef
178.
Romagnoli R, Prencipe F, Oliva P, Baraldi S, Baraldi PG, Schiaffino Ortega S, et al. Design, synthesis, and biological evaluation of 6-substituted thieno[3,2-d]pyrimidine analogues as dual epidermal growth factor receptor kinase and microtubule inhibitors. J Med Chem. 2019;62:1274–90.PubMedCrossRef
179.
Alswah M, Bayoumi AH, Elgamal K, Elmorsy A, Ihmaid S, Ahmed HEA. Design, synthesis and cytotoxic evaluation of novel chalcone derivatives bearing triazolo[4,3-a]-quinoxaline moieties as potent anticancer agents with dual EGFR kinase and tubulin polymerization inhibitory effects. Molecules. 2017;23:48.PubMedCentralCrossRef
180.
Khan I, Garikapati KR, Setti A, Shaik AB, Kanth Makani VK, Shareef MA, et al. Design, synthesis, in silico pharmacokinetics prediction and biological evaluation of 1,4-dihydroindeno[1,2-c]pyrazole chalcone as EGFR/AKT pathway inhibitors. Eur J Med Chem. 2019;163:636–48.PubMedCrossRef
181.
Dong H, Yin H, Zhao C, Cao J, Xu W, Zhang Y. Design, synthesis and biological evaluation of novel osimertinib-based HDAC and EGFR dual inhibitors. Molecules. 2019;24:2407.PubMedCentralCrossRef
182.
Fischer T, Najjar A, Totzke F, Schachtele C, Sippl W, Ritter C, et al. Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance. J Enzyme Inhib Med Chem. 2018;33:1–8.PubMedCrossRef
183.
Hamed MM, Darwish SS, Herrmann J, Abadi AH, Engel M. First bispecific inhibitors of the epidermal growth factor receptor kinase and the NF-κB activity as novel anticancer agents. J Med Chem. 2017;60:2853–68.PubMedCrossRef
184.
Dokla EME, Fang CS, Abouzid KAM, Chen CS. 1,2,4-oxadiazole derivatives targeting EGFR and c-Met degradation in TKI resistant NSCLC. Eur J Med Chem. 2019;182:111607.PubMedCrossRef
185.
Singh PK, Silakari O. Molecular dynamics guided development of indole based dual inhibitors of EGFR (T790M) and c-Met. Bioorg Chem. 2018;79:163–70.PubMedCrossRef
186.
Fischer T, Kruger T, Najjar A, Totzke F, Schachtele C, Sippl W, et al. Discovery of novel substituted benzo-anellated 4-benzylamino pyrrolopyrimidines as dual EGFR and vEGFR2 inhibitors. Bioorg Med Chem Lett. 2017;27:2708–12.PubMedCrossRef
187.
Zhang HQ, Gong FH, Ye JQ, Zhang C, Yue XH, Li CG, et al. Design and discovery of 4-anilinoquinazoline-urea derivatives as dual TK inhibitors of EGFR and vEGFR-2. Eur J Med Chem. 2017;125:245–54.PubMedCrossRef
188.
Wei H, Duan Y, Gou W, Cui J, Ning H, Li D, et al. Design, synthesis and biological evaluation of novel 4-anilinoquinazoline derivatives as hypoxia-selective EGFR and vEGFR-2 dual inhibitors. Eur J Med Chem. 2019;181:111552.PubMedCrossRef
189.
Sun S, Zhang J, Wang N, Kong X, Fu F, Wang H, et al. Design and discovery of quinazoline- and thiourea-containing sorafenib analogs as EGFR and vEGFR-2 dual TK inhibitors. Molecules. 2017;23:24.PubMedCentralCrossRef
190.
Das D, Xie L, Wang J, Xu X, Zhang Z, Shi J, et al. Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities: part 1. Bioorg Med Chem Lett. 2019;29:591–6.PubMedCrossRef
191.
Maher M, Kassab AE, Zaher AF, Mahmoud Z. Novel pyrazolo[3,4-d]pyrimidines: design, synthesis, anticancer activity, dual EGFR/ErbB2 receptor tyrosine kinases inhibitory activity, effects on cell cycle profile and caspase-3-mediated apoptosis. J Enzyme Inhib Med Chem. 2019;34:532–46.PubMedPubMedCentralCrossRef
192.
Zou M, Li J, Jin B, Wang M, Chen H, Zhang Z, et al. Design, synthesis and anticancer evaluation of new 4-anilinoquinoline-3-carbonitrile derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers. Bioorg Chem. 2021;114:105200.PubMedCrossRef
193.
Alsaid MS, Al-Mishari AA, Soliman AM, Ragab FA, Ghorab MM. Discovery of benzo[g]quinazolin benzenesulfonamide derivatives as dual EGFR/HER2 inhibitors. Eur J Med Chem. 2017;141:84–91.PubMedCrossRef
194.
Ghorab MM, Alsaid MS, Soliman AM. Dual EGFR/HER2 inhibitors and apoptosis inducers: new benzo[g]quinazoline derivatives bearing benzenesulfonamide as anticancer and radiosensitizers. Bioorg Chem. 2018;80:611–20.PubMedCrossRef
195.
Soliman AM, Alqahtani AS, Ghorab M. Novel sulphonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers. J Enzyme Inhib Med Chem. 2019;34:1030–40.PubMedPubMedCentralCrossRef
196.
Liu X, Du Q, Tian C, Tang M, Jiang Y, Wang Y, et al. Discovery of cape derivatives as dual EGFR and CSK inhibitors with anticancer activity in a murine model of hepatocellular carcinoma. Bioorg Chem. 2021;107:104536.PubMedCrossRef
197.
Zhang B, Liu Z, Xia S, Liu Q, Gou S. Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors. Eur J Med Chem. 2021;216:113300.PubMedCrossRef
198.
Zang H, Qian G, Arbiser J, Owonikoko TK, Ramalingam SS, Fan S, et al. Overcoming acquired resistance of EGFR-mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol. Mol Oncol. 2020;14:882–95.PubMedPubMedCentralCrossRef
199.
Cao F, Gong YB, Kang XH, Lu ZH, Wang Y, Zhao KL, et al. Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer. Toxicol Appl Pharmacol. 2019;379:114662.PubMedCrossRef
200.
Sun P, Qu Y, Wang Y, Wang J, Wang X, Sheng J. Wighteone exhibits an antitumor effect against EGFR L858R/T790M mutation non-small cell lung cancer. J Cancer. 2021;12:3900–8.PubMedPubMedCentralCrossRef
201.
Niu M, Xu J, Liu Y, Li Y, He T, Ding L, et al. FBXL 2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth. Nat Commun. 2021;12:5919.PubMedPubMedCentralCrossRef
202.
Zhang KR, Zhang YF, Lei HM, Tang YB, Ma CS, Lv QM, et al. Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer. Sci Transl Med. 2021;13:eabg6428.PubMedCrossRef
203.
Hitosugi T, Zhou L, Elf S, Fan J, Kang HB, Seo JH, et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012;22:585–600.PubMedPubMedCentralCrossRef
204.
Liang Q, Gu WM, Huang K, Luo MY, Zou JH, Zhuang GL, et al. HKB99, an allosteric inhibitor of phosphoglycerate mutase 1, suppresses invasive pseudopodia formation and upregulates plasminogen activator inhibitor-2 in erlotinib-resistant non-small cell lung cancer cells. Acta Pharmacol Sin. 2021;42:115–9.PubMedCrossRef
205.
Huang K, Liang Q, Zhou Y, Jiang LL, Gu WM, Luo MY, et al. A novel allosteric inhibitor of phosphoglycerate mutase 1 suppresses growth and metastasis of non-small-cell lung cancer. Cell Metab. 2021;33:223.PubMedCrossRef
206.
Huang K, Liang Q, Zhou Y, Jiang L-l, Gu W-m, Luo M-y, et al. A novel allosteric inhibitor of phosphoglycerate mutase 1 suppresses growth and metastasis of non-small-cell lung cancer. Cell Metab. 2019;30:1107-19.e8.PubMedCrossRef
207.
Qiu Y, Yin X, Li X, Wang Y, Fu Q, Huang R, et al. Untangling dual-targeting therapeutic mechanism of epidermal growth factor receptor (EGFR) based on reversed allosteric communication. Pharmaceutics. 2021;13:747.PubMedPubMedCentralCrossRef
208.
Yin L, Zhang Y, Yin L, Ou Y, Lewis MS, Wang R, et al. Novel mitochondria-based targeting restores responsiveness in therapeutically resistant human lung cancer cells. Mol Cancer Ther. 2021;20(12):2527–38.PubMedCrossRef
209.
He J, Huang Z, Han L, Gong Y, Xie C. Mechanisms and management of 3rd-generation EGFR-TKI resistance in advanced non-small cell lung cancer (Review). Int J Oncol. 2021;59:90.PubMedPubMedCentralCrossRef
210.
Planchard D, Feng PH, Karaseva N, Kim SW, Kim TM, Lee CK, et al. Osimertinib plus platinum–pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study. ESMO Open. 2020;6:100271.CrossRef
211.
Yi M, Zheng X, Niu M, Zhu S, Ge H, Wu K. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer. 2022;21:28.PubMedPubMedCentralCrossRef
212.
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078–92.PubMedCrossRef
213.
Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379:2040–51.PubMedCrossRef
214.
Zhou C, Wu L, Fan Y, Wang Z, Liu L, Chen G, et al. Sintilimab plus platinum and gemcitabine as first-line treatment for advanced or metastatic squamous nsclc: results from a randomized, double-blind, phase 3 trial (ORIENT-12). J Thorac Oncol. 2021;16:1501–11.PubMedCrossRef
215.
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288–301.PubMedCrossRef
216.
Jabbour SK, Berman AT, Decker RH, Lin Y, Feigenberg SJ, Gettinger SN, et al. Phase 1 trial of pembrolizumab administered concurrently with chemoradiotherapy for locally advanced non-small cell lung cancer: a nonrandomized controlled trial. JAMA Oncol. 2020;6:848–55.PubMedCrossRef
217.
Liu D, Gong J, Liu T, Li K, Yin X, Liu Y, et al. Phase 1 study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced solid tumors. J Clin Oncol. 2021;39:2503–2503.CrossRef
218.
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Trans Med. 2011;3:75ra26.CrossRef
219.
Wu L, Ke L, Zhang Z, Yu J, Meng X. Development of EGFR TKIs and options to manage resistance of third-generation EGFR TKI osimertinib: conventional ways and immune checkpoint inhibitors. Front Oncol. 2020;10:602762–862.PubMedPubMedCentralCrossRef
Metadata
Title
Emerging strategies to overcome resistance to third-generation EGFR inhibitors
Authors
Kunyu Shi
Guan Wang
Junping Pei
Jifa Zhang
Jiaxing Wang
Liang Ouyang
Yuxi Wang
Weimin Li
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2022
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-022-01311-6

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