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

Open Access 01-12-2022 | NSCLC | Review

Drugging KRAS: current perspectives and state-of-art review

Authors: Kaushal Parikh, Giuseppe Banna, Stephen V. Liu, Alex Friedlaender, Aakash Desai, Vivek Subbiah, Alfredo Addeo

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

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Abstract

After decades of efforts, we have recently made progress into targeting KRAS mutations in several malignancies. Known as the ‘holy grail’ of targeted cancer therapies, KRAS is the most frequently mutated oncogene in human malignancies. Under normal conditions, KRAS shuttles between the GDP-bound ‘off’ state and the GTP-bound ‘on’ state. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Simultaneously, effects of KRAS mutations on tumour microenvironment were also discovered, partly owing to the universal use of immune checkpoint inhibitors. In this review, we discuss the discovery, biology, and function of KRAS in human malignancies. We also discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS. Finally, we review the current clinical evidence and ongoing clinical trials of novel agents targeting KRAS and shine light on resistance pathways known so far.
Literature
1.
Sung H, Ferlay J, Siegel RL, Global Cancer Statistics 2020, et al. GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.PubMedCrossRef
2.
Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703–13.PubMedPubMedCentralCrossRef
3.
Uprety D, Parikh K, Sawkar A, Dimou A, Leventakos K. Changing paradigm in advanced and metastatic non-small cell lung cancer. J Thorac Dis. 2020;12(11):6992–7001.PubMedPubMedCentralCrossRef
4.
Kinsey CG, Camolotto SA, Boespflug AM, et al. Protective autophagy elicited by RAF–>MEK–>ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019;25(4):620–7.PubMedPubMedCentralCrossRef
5.
Harvey JJ. An unidentified virus which causes the rapid production of tumours in mice. Nature. 1964;204:1104–5.PubMedCrossRef
6.
Kirsten WH, Mayer LA. Morphologic responses to a murine erythroblastosis virus. J Natl Cancer Inst. 1967;39(2):311–35.PubMed
7.
Shih TY, Weeks MO, Young HA, Scholnick EM. Identification of a sarcoma virus-coded phosphoprotein in nonproducer cells transformed by Kirsten or Harvey murine sarcoma virus. Virology. 1979;96(1):64–79.PubMedCrossRef
8.
Scolnick EM, Papageorge AG, Shih TY. Guanine nucleotide-binding activity as an assay for src protein of rat-derived murine sarcoma viruses. Proc Natl Acad Sci U S A. 1979;76(10):5355–9.PubMedPubMedCentralCrossRef
9.
10.
Der CJ, Krontiris TG, Cooper GM. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Natl Acad Sci U S A. 1982;79(11):3637–40.PubMedPubMedCentralCrossRef
11.
Hall A, Marshall CJ, Spurr NK, Weiss RA. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1. Nature. 1983;303(5916):396–400.PubMedCrossRef
12.
Santos E, Martin-Zanca D, Reddy EP, Pierotti MA, Della Porta G, Barbacid M. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science. 1984;223(4637):661–4.PubMedCrossRef
13.
Nakano H, Yamamoto F, Neville C, Evans D, Mizuno T, Perucho M. Isolation of transforming sequences of two human lung carcinomas: structural and functional analysis of the activated c-K-ras oncogenes. Proc Natl Acad Sci U S A. 1984;81(1):71–5.PubMedPubMedCentralCrossRef
14.
Popescu NC, Amsbaugh SC, DiPaolo JA, Tronick SR, Aaronson SA, Swan DC. Chromosomal localization of three human ras genes by in situ molecular hybridization. Somat Cell Mol Genet. 1985;11(2):149–55.PubMedCrossRef
15.
Capon DJ, Seeburg PH, McGrath JP, et al. Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations. Nature. 1983;304(5926):507–13.PubMedCrossRef
16.
Sweet RW, Yokoyama S, Kamata T, Feramisco JR, Rosenberg M, Gross M. The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature. 1984;311(5983):273–5.PubMedCrossRef
17.
18.
Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: conserved structure and molecular mechanism. Nature. 1991;349(6305):117–27.PubMedCrossRef
19.
Kato K, Cox AD, Hisaka MM, Graham SM, Buss JE, Der CJ. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci U S A. 1992;89(14):6403–7.PubMedPubMedCentralCrossRef
20.
Clarke S. Protein isoprenylation and methylation at carboxyl-terminal cysteine residues. Annu Rev Biochem. 1992;61:355–86.PubMedCrossRef
21.
Nan X, Tamguney TM, Collisson EA, et al. Ras-GTP dimers activate the mitogen-activated protein kinase (MAPK) pathway. Proc Natl Acad Sci U S A. 2015;112(26):7996–8001.PubMedPubMedCentralCrossRef
22.
Broek D, Toda T, Michaeli T, et al. The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway. Cell. 1987;48(5):789–99.PubMedCrossRef
23.
Bonfini L, Karlovich CA, Dasgupta C, Banerjee U. The Son of sevenless gene product: a putative activator of Ras. Science. 1992;255(5044):603–6.PubMedCrossRef
24.
Wei W, Mosteller RD, Sanyal P, et al. Identification of a mammalian gene structurally and functionally related to the CDC25 gene of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1992;89(15):7100–4.PubMedPubMedCentralCrossRef
25.
Bowtell D, Fu P, Simon M, Senior P. Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras. Proc Natl Acad Sci U S A. 1992;89(14):6511–5.PubMedPubMedCentralCrossRef
26.
Buday L, Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell. 1993;73(3):611–20.PubMedCrossRef
27.
Chardin P, Camonis JH, Gale NW, et al. Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993;260(5112):1338–43.PubMedCrossRef
28.
Gale NW, Kaplan S, Lowenstein EJ, Schlessinger J, Bar-Sagi D. Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature. 1993;363(6424):88–92.PubMedCrossRef
29.
Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature. 1993;363(6424):45–51.PubMedCrossRef
30.
Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J. The structural basis of the activation of Ras by Sos. Nature. 1998;394(6691):337–43.PubMedCrossRef
31.
Dance M, Montagner A, Salles JP, Yart A, Raynal P. The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal. 2008;20(3):453–9.PubMedCrossRef
32.
Shi ZQ, Yu DH, Park M, Marshall M, Feng GS. Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity. Mol Cell Biol. 2000;20(5):1526–36.PubMedPubMedCentralCrossRef
33.
Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29(4):465–8.PubMedCrossRef
34.
Trahey M, McCormick F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science. 1987;238(4826):542–5.PubMedCrossRef
35.
Takacs T, Kudlik G, Kurilla A, Szeder B, Buday L, Vas V. The effects of mutant Ras proteins on the cell signalome. Cancer Metastasis Rev. 2020;39(4):1051–65.PubMedPubMedCentralCrossRef
36.
37.
38.
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204.PubMedCrossRef
39.
Hofer F, Fields S, Schneider C, Martin GS. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc Natl Acad Sci U S A. 1994;91(23):11089–93.PubMedPubMedCentralCrossRef
40.
Lambert JM, Lambert QT, Reuther GW, et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat Cell Biol. 2002;4(8):621–5.PubMedCrossRef
41.
Yokota J, Kohno T. Molecular footprints of human lung cancer progression. Cancer Sci. 2004;95(3):197–204.PubMedCrossRef
42.
Lohr M, Kloppel G, Maisonneuve P, Lowenfels AB, Luttges J. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia. 2005;7(1):17–23.PubMedPubMedCentralCrossRef
43.
44.
Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res. 2015;13(9):1325–35.PubMedCrossRef
45.
Rabara D, Tran TH, Dharmaiah S, et al. KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. Proc Natl Acad Sci U S A. 2019;116(44):22122–31.PubMedPubMedCentralCrossRef
46.
Ihle NT, Byers LA, Kim ES, et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst. 2012;104(3):228–39.PubMedPubMedCentralCrossRef
47.
Friedlaender A, Drilon A, Weiss GJ, Banna GL, Addeo A. KRAS as a druggable target in NSCLC: rising like a phoenix after decades of development failures. Cancer Treat Rev. 2020;85:101978.PubMedPubMedCentralCrossRef
48.
Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res. 2012;18(22):6169–77.PubMedPubMedCentralCrossRef
49.
50.
51.
52.
Scheffler M, Ihle MA, Hein R, et al. K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways. J Thorac Oncol. 2019;14(4):606–16.PubMedCrossRef
53.
Judd J, Abdel Karim N, Khan H, et al. Characterization of KRAS mutation subtypes in non-small cell lung cancer. Mol Cancer Ther. 2021;20(12):2577–84.PubMedCrossRef
54.
Bange E, Marmarelis ME, Hwang WT, et al. Impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy among patients with STK11-mutated advanced non-small-cell lung cancer. JCO Precis Oncol. 2019;3:PO.18.00326
55.
56.
Arbour KC, Jordan E, Kim HR, et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin Cancer Res. 2018;24(2):334–40.PubMedCrossRef
57.
Shepherd FA, Lacas B, Le Teuff G, et al. pooled analysis of the prognostic and predictive effects of TP53 comutation status combined with KRAS or EGFR mutation in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol. 2017;35(18):2018–27.PubMedPubMedCentralCrossRef
58.
Tomasini P, Mascaux C, Jao K, et al. Effect of coexisting KRAS and TP53 mutations in patients treated with chemotherapy for non-small-cell lung cancer. Clin Lung Cancer. 2019;20(3):e338–45.PubMedCrossRef
59.
Del Re M, Tiseo M, Bordi P, et al. Contribution of KRAS mutations and c.2369C > T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA. Oncotarget. 2017;8(8):13611–9.PubMedCrossRef
60.
Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18(5):1472–82.PubMedPubMedCentralCrossRef
61.
Niemantsverdriet M, Schuuring E, Elst AT, et al. KRAS mutation as a resistance mechanism to BRAF/MEK inhibition in NSCLC. J Thorac Oncol. 2018;13(12):e249–51.PubMedCrossRef
62.
63.
64.
65.
Zhang W, Nandakumar N, Shi Y, et al. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci Signal. 2014;7(324):ra42.PubMedPubMedCentralCrossRef
66.
67.
Gu M, Gao Y, Chang P. KRAS mutation dictates the cancer immune environment in pancreatic ductal adenocarcinoma and other adenocarcinomas. Cancers (Basel). 2021;13(10):2429.PubMedPubMedCentralCrossRef
68.
O’Reilly EM, Oh DY, Dhani N, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 Randomized Clinical Trial. JAMA Oncol. 2019;5(10):1431–8.PubMedPubMedCentralCrossRef
69.
Liao W, Overman MJ, Boutin AT, et al. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell. 2019;35(4):559-572.e557.PubMedPubMedCentralCrossRef
70.
Liu J, Huang X, Liu H, et al. Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients. J Transl Med. 2021;19(1):27.PubMedPubMedCentralCrossRef
71.
Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23.PubMedCrossRef
72.
Skoulidis F, Byers LA, Diao L, et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 2015;5(8):860–77.PubMedPubMedCentralCrossRef
73.
Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 2018;8(7):822–35.PubMedPubMedCentralCrossRef
74.
Ricciuti B, Arbour KC, Lin JJ, et al. Diminished efficacy of programmed death-(Ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status. J Thorac Oncol. 2022;17(3):399–410.PubMedCrossRef
75.
LoRusso PM, Sebolt-Leopold JS. One step at a time—clinical evidence that KRAS Is indeed druggable. N Engl J Med. 2020;383(13):1277–8.PubMedCrossRef
76.
Liu M, Bryant MS, Chen J, et al. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res. 1998;58(21):4947–56.PubMed
77.
Adjei AA, Erlichman C, Davis JN, et al. A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res. 2000;60(7):1871–7.PubMed
78.
Adjei AA, Croghan GA, Erlichman C, et al. A phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer. Clin Cancer Res. 2003;9(7):2520–6.PubMed
79.
Zhang FL, Kirschmeier P, Carr D, et al. Characterization of Ha-ras, N-ras, Ki-Ras4A, and Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I. J Biol Chem. 1997;272(15):10232–9.PubMedCrossRef
80.
Adjei AA, Mauer A, Bruzek L, et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2003;21(9):1760–6.PubMedCrossRef
81.
82.
83.
Riely GJ, Johnson ML, Medina C, et al. A phase II trial of salirasib in patients with lung adenocarcinomas with KRAS mutations. J Thorac Oncol. 2011;6(8):1435–7.PubMedCrossRef
84.
Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51.PubMedPubMedCentralCrossRef
85.
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. ChemMedChem. 2007;2(1):58–61.PubMedCrossRef
86.
Gonzales AJ, Hook KE, Althaus IW, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2008;7(7):1880–9.PubMedCrossRef
87.
Lim SM, Westover KD, Ficarro SB, et al. Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor. Angew Chem Int Ed Engl. 2014;53(1):199–204.PubMedCrossRef
88.
Xiong Y, Lu J, Hunter J, et al. Covalent guanosine mimetic inhibitors of G12C KRAS. ACS Med Chem Lett. 2017;8(1):61–6.PubMedCrossRef
89.
Patricelli MP, Janes MR, Li LS, et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 2016;6(3):316–29.PubMedCrossRef
90.
Janes MR, Zhang J, Li LS, et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell. 2018;172(3):578-589.e517.PubMedCrossRef
91.
Hallin J, Engstrom LD, Hargis L, et al. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54–71.PubMedCrossRef
92.
Fell JB, Fischer JP, Baer BR, et al. Identification of the clinical development candidate MRTX849, a covalent KRAS(G12C) inhibitor for the treatment of cancer. J Med Chem. 2020;63(13):6679–93.PubMedCrossRef
93.
94.
95.
96.
Johnson ML, de Langen AJ, Waterhouse DM, et al. LBA10 Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. Ann Oncol. 2022;33:S1417–8.CrossRef
97.
Fakih MG, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRAS(G12C) mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022;23(1):115–24.PubMedCrossRef
98.
Strickler JH, Satake H, Hollebecque A, et al. First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: a phase I/II study evaluating efficacy and safety. J Clin Oncol. 2022;40(36):360490–360490.CrossRef
99.
Ou SI, Janne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS(G12C) solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530–38. 
100.
Janne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation. N Engl J Med. 2022;387(2):120–31. 
101.
Sabari JK, Velcheti V, Shimizu K, et al. Activity of adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with KRAS G12C-mutant non-small cell lung cancer. Clin Cancer Res. 2022;28(15):3318–28. 
102.
Weiss J, Yaeger RD, Johnson ML, et al. LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32:S1294.CrossRef
103.
104.
Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(15):9003–9003.CrossRef
105.
106.
107.
Singh A, Greninger P, Rhodes D, et al. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009;15(6):489–500.PubMedPubMedCentralCrossRef
108.
Adachi Y, Ito K, Hayashi Y, et al. Epithelial-to-mesenchymal transition is a cause of both intrinsic and acquired resistance to KRAS G12C inhibitor in KRAS G12C-mutant non-small cell lung cancer. Clin Cancer Res. 2020;26(22):5962–73.PubMedCrossRef
109.
Tanaka N, Lin JJ, Li C, et al. Clinical acquired resistance to KRAS(G12C) inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. 2021;11(8):1913–22.PubMedPubMedCentralCrossRef
110.
Hofmann MH, Gerlach D, Misale S, Petronczki M, Kraut N. Expanding the reach of precision oncology by drugging all KRAS mutants. Cancer Discov. 2022;12(4):924–37.PubMedPubMedCentralCrossRef
111.
Vaclova T, Chakraborty A, Sherwood J, et al. Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition. Sci Rep. 2022;12(1):2699.PubMedPubMedCentralCrossRef
112.
Cannataro VL, Gaffney SG, Stender C, et al. Heterogeneity and mutation in KRAS and associated oncogenes: evaluating the potential for the evolution of resistance to targeting of KRAS G12C. Oncogene. 2018;37(18):2444–55.PubMedCrossRef
113.
114.
115.
Lito P, Pratilas CA, Joseph EW, et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell. 2012;22(5):668–82.PubMedPubMedCentralCrossRef
116.
Ryan MB, de la Cruz FF, Phat S, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition. Clin Cancer Res. 2020;26(7):1633–43.PubMedCrossRef
117.
Amodio V, Yaeger R, Arcella P, et al. EGFR blockade reverts resistance to KRAS(G12C) inhibition in colorectal cancer. Cancer Discov. 2020;10(8):1129–39.PubMedPubMedCentralCrossRef
118.
Suzuki S, Yonesaka K, Teramura T, et al. KRAS inhibitor resistance in MET-amplified KRAS (G12C) non-small cell lung cancer induced by RAS- and non-RAS-mediated cell signaling mechanisms. Clin Cancer Res. 2021;27(20):5697–707.PubMedCrossRef
119.
Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100–3.PubMedCrossRef
120.
121.
Zhang B, Zhang Y, Zhang J, et al. Focal adhesion kinase (FAK) inhibition synergizes with KRAS G12C inhibitors in treating cancer through the regulation of the FAK-YAP signaling. Adv Sci (Weinh). 2021;8(16):e2100250.CrossRef
122.
123.
124.
Wang X, Allen S, Blake JF, et al. Identification of MRTX1133, a noncovalent, potent, and selective KRAS(G12D) Inhibitor. J Med Chem. 2022;65(4):3123–33.PubMedCrossRef
125.
Knox JE, Jiang J, Burnett GL, et al. Abstract 3596: RM-036, a first-in-class, orally-bioavailable, Tri-Complex covalent KRASG12D(ON) inhibitor, drives profound anti-tumor activity in KRASG12D mutant tumor models. Cancer Res. 2022;82(12_Supplement):3596–3596.CrossRef
126.
Nichols RJ, Yang YC, Cregg J, et al. Abstract 3595: RMC-6291, a next-generation tri-complex KRASG12C(ON) inhibitor, outperforms KRASG12C(OFF) inhibitors in preclinical models of KRASG12C cancers. Cancer Res. 2022;82(12_Supplement):3595–3595.CrossRef
127.
Schulze CJ, Cregg J, Seamon KJ, et al. Abstract 3598: a first-in-class tri-complex KRASG13C(ON) inhibitor validates therapeutic targeting of KRASG13Cand drives tumor regressions in preclinical models. Cancer Res. 2022;82(12):3598–3598.CrossRef
128.
Koltun ES, Rice MA, Gustafson WC, et al. Abstract 3597: direct targeting of KRASG12X mutant cancers with RMC-6236, a first-in-class, RAS-selective, orally bioavailable, tri-complex RASMULTI(ON) inhibitor. Cancer Res. 2022;82(12_Supplement):3597–3597.CrossRef
129.
Hainsworth JD, Cebotaru CL, Kanarev V, et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol. 2010;5(10):1630–6.PubMedCrossRef
130.
Blumenschein GR Jr, Smit EF, Planchard D, et al. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC) dagger. Ann Oncol. 2015;26(5):894–901.PubMedPubMedCentralCrossRef
131.
Janne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38–47.PubMedCrossRef
132.
Janne PA, van den Heuvel MM, Barlesi F, et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: The SELECT-1 randomized clinical trial. JAMA. 2017;317(18):1844–53.PubMedPubMedCentralCrossRef
133.
Froesch P, Mark M, Rothschild SI, et al. Binimetinib, pemetrexed and cisplatin, followed by maintenance of binimetinib and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) and KRAS mutations. The phase 1B SAKK 19/16 trial. Lung Cancer. 2021;156:91–9.PubMedCrossRef
134.
Puyol M, Martin A, Dubus P, et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell. 2010;18(1):63–73.PubMedCrossRef
135.
Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov. 2016;6(7):740–53.PubMedCrossRef
136.
Goldman JW, Mazieres J, Barlesi F, et al. A randomized phase III study of abemaciclib versus erlotinib in patients with stage IV non-small cell lung cancer with a detectable KRAS mutation who failed prior platinum-based therapy: JUNIPER. Front Oncol. 2020;10:578756.PubMedPubMedCentralCrossRef
137.
Hayes TK, Neel NF, Hu C, et al. Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression. Cancer Cell. 2016;29(1):75–89.PubMedCrossRef
138.
Sullivan RJ, Infante JR, Janku F, et al. First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study. Cancer Discov. 2018;8(2):184–95.PubMedCrossRef
139.
Pant S, Bendell JC, Sullivan RJ, et al. A phase I dose escalation (DE) study of ERK inhibitor, LY3214996, in advanced (adv) cancer (CA) patients (pts). J Clin Oncol. 2019;37(15):3001–3001.CrossRef
140.
Janku F, Elez E, Iyer G, et al. Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations. J Clin Oncol. 2020;38(15_suppl):3640–3640.CrossRef
141.
Li A, Jian S, Yuan X, et al. Abstract 4188: the ERK1/2 inhibitor, JSI-1187, demonstrates preclinical efficacy in tumor models with MAPK pathway mutations. Cancer Res. 2020;80(16_Supplement):4188–4188.CrossRef
142.
Ramalingam S, Fakih M, Strickler J, et al. Abstract P05-01: a phase 1b study evaluating the safety and efficacy of sotorasib, a KRASG12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-mutated solid tumors. Mol Cancer Ther. 2021;20(12_Supplement):P05-01-P05-01.CrossRef
143.
Lito P, Saborowski A, Yue J, et al. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell. 2014;25(5):697–710.PubMedPubMedCentralCrossRef
144.
Guo C, Chenard-Poirier M, Roda D, et al. Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. Lancet Oncol. 2020;21(11):1478–88.PubMedCrossRef
145.
Krebs MG, Shinde R, Rahman RA, et al. Abstract CT019: a phase I trial of the combination of the dual RAF-MEK inhibitor VS-6766 and the FAK inhibitor defactinib: evaluation of efficacy in KRAS mutated NSCLC. Cancer Res. 2021;81(13):CT019–CT019.CrossRef
146.
Fakih M, Falchook GS, Hong DS, et al. 434P CodeBreaK 101 subprotocol H: phase Ib study evaluating combination of sotorasib (Soto), a KRASG12C inhibitor, and panitumumab (PMab), an EGFR inhibitor, in advanced KRAS p.G12C-mutated colorectal cancer (CRC). Ann Oncol. 2021;32:S551.CrossRef
147.
Gandara D, Marrone K, Govindan R, et al. Abstract P05–02: a phase 1b study evaluating the combination of sotorasib, a KRASG12C inhibitor, and afatinib, a pan-ErbB tyrosine kinase inhibitor, in advanced KRAS p.G12C mutated non-small cell lung cancer (NSCLC). Mol Cancer Ther. 2021;20(12_Supplement):P05-02-P05-02.CrossRef
148.
Hillig RC, Sautier B, Schroeder J, et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci USA. 2019;116(7):2551–60.PubMedPubMedCentralCrossRef
149.
Hofmann MH, Gmachl M, Ramharter J, et al. BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov. 2021;11(1):142–57.PubMedCrossRef
150.
151.
Johnson ML, Gort E, Pant S, et al. 524P A phase I, open-label, dose-escalation trial of BI 1701963 in patients (pts) with KRAS mutated solid tumours: a snapshot analysis. Ann Oncol. 2021;32:S591–2.CrossRef
152.
Ketcham JM, Khare S, et al. Abstract ND02: MRTX0902: a SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers. Cancer Res. 2022;82(12_Supplement):ND02–ND02.CrossRef
153.
Chen YN, LaMarche MJ, Chan HM, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016;535(7610):148–52.PubMedCrossRef
154.
Mainardi S, Mulero-Sanchez A, Prahallad A, et al. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat Med. 2018;24(7):961–7.PubMedCrossRef
155.
Ruess DA, Heynen GJ, Ciecielski KJ, et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med. 2018;24(7):954–60.PubMedCrossRef
156.
Fedele C, Ran H, Diskin B, et al. SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models. Cancer Discov. 2018;8(10):1237–49.PubMedPubMedCentralCrossRef
157.
Nichols RJ, Haderk F, Stahlhut C, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol. 2018;20(9):1064–73.PubMedPubMedCentralCrossRef
158.
Liu C, Lu H, Wang H, et al. Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin Cancer Res. 2021;27(1):342–54.PubMedCrossRef
159.
Ou SI, Koczywas M, Ulahannan S, et al. A12 the SHP2 inhibitor RMC-4630 in patients with KRAS-mutant non-small cell lung cancer: preliminary evaluation of a First-in-man phase 1 clinical trial. J Thorac Oncol. 2020;15(2):S15–6.CrossRef
160.
Falchook GS LB, Marrone KA, Bestvina CM, Langer CJ, Krauss JC, Strickler JH, Meloni AR, Dai T, Varrieur T, Hong DS. Sotorasib in Combination with RMC-4630, a SHP2 Inhibitor, in KRAS p.G12C-Mutated NSCLC and Other Solid Tumors. Paper presented at: World Conference on Lung Cancer2022; Vienna, Austria.
161.
Briere DM, Li S, Calinisan A, et al. The KRAS(G12C) inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. Mol Cancer Ther. 2021;20(6):975–85.PubMedPubMedCentralCrossRef
162.
Mugarza E, van Maldegem F, Boumelha J, et al. Therapeutic KRAS(G12C) inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. Sci Adv. 2022;8(29):eabm8780.PubMedPubMedCentralCrossRef
163.
Li BT FG, Durm GA, Burns TF, Skoulidis F, Ramalingam SS, Spira A, Bestvina CM, Goldberg SB, Veluswamy R, Iams WT, Chiappori AA, Lemech CR, Meloni AR, Ebiana VA, Dai T, Gauto DM, VVarrieur TL, Snyder WJ, Govindan R. CodeBreaK 100/101: First report of safety and efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. Paper presented at: World Conference on Lung Cancer2022; Vienna, Austria.
164.
Begum P, Goldin RD, Possamai LA, Popat S. Severe Immune checkpoint inhibitor hepatitis in KRAS G12C-mutant NSCLC potentially triggered by sotorasib: case report. JTO Clin Res Rep. 2021;2(9):100213.PubMedPubMedCentral
165.
Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209(6):1201–17.PubMedPubMedCentralCrossRef
166.
Zhao M, Guo W, Wu Y, et al. SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade. Acta Pharm Sin B. 2019;9(2):304–15.PubMedCrossRef
167.
Wang Y, Mohseni M, Grauel A, et al. SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms. Sci Rep. 2021;11(1):1399.PubMedPubMedCentralCrossRef
168.
Zhang Z, Morstein J, Ecker AK, Guiley KZ, Shokat KM. Chemoselective covalent modification of K-Ras (G12R) with a small molecule electrophile. J Am Chem Soc. 2022;144(35):15916–21.PubMedPubMedCentralCrossRef
169.
170.
Gjertsen MK, Bakka A, Breivik J, et al. Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study. Int J Cancer. 1996;65(4):450–3.PubMedCrossRef
171.
Khleif SN, Abrams SI, Hamilton JM, et al. A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. J Immunother. 1999;22(2):155–65.PubMedCrossRef
172.
Bond MJ, Chu L, Nalawansha DA, Li K, Crews CM. Targeted degradation of oncogenic KRAS(G12C) by VHL-recruiting PROTACs. ACS Cent Sci. 2020;6(8):1367–75.PubMedPubMedCentralCrossRef
173.
Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.PubMedCrossRef
174.
Campbell JD, Alexandrov A, Kim J, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet. 2016;48(6):607–16.PubMedPubMedCentralCrossRef
175.
Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–50.CrossRef
176.
177.
178.
Yaeger R, Chatila WK, Lipsyc MD, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer. Cancer Cell. 2018;33(1):125-136.e123.PubMedPubMedCentralCrossRef
179.
Boerner T, Drill E, Pak LM, et al. Genetic determinants of outcome in intrahepatic cholangiocarcinoma. Hepatology. 2021;74(3):1429–44.PubMedCrossRef
180.
Jusakul A, Cutcutache I, Yong CH, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 2017;7(10):1116–35.PubMedPubMedCentralCrossRef
181.
Cancer Genome Atlas Research Network, Analysis Working Group, Asan U, Agency BCC, et al. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017;541(7636):169–75.CrossRef
182.
Janjigian YY, Sanchez-Vega F, Jonsson P, et al. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov. 2018;8(1):49–58.PubMedCrossRef
183.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.CrossRef
Metadata
Title
Drugging KRAS: current perspectives and state-of-art review
Authors
Kaushal Parikh
Giuseppe Banna
Stephen V. Liu
Alex Friedlaender
Aakash Desai
Vivek Subbiah
Alfredo Addeo
Publication date
01-12-2022
Publisher
BioMed Central
Keywords
NSCLC
NSCLC
Published in
Journal of Hematology & Oncology / Issue 1/2022
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-022-01375-4

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