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Review Article | Open Access

Covalent inhibitor targets KRasG12C: A new paradigm for drugging the undruggable and challenges ahead

Hui-yu Lia,b,1, Wei-liang Qia,b,c,1, Yu-xiang Wanga,( ), Ling-hua Menga,b( )
Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
University of Chinese Academy of Sciences, Beijing 100049, China
College of Pharmacy, Nanchang University, Nanchang, Jiangxi 330006, China

1 These authors contributed equally to this work.

Peer review under responsibility of Chongqing Medical University.

Show Author Information

Abstract

KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging. Among the different known mutants, KRasG12C has been proved to be successfully targeted recently. Several covalent inhibitors selectively targeting KRasG12C have shown promising efficacy against cancers harboring KRASG12C mutation in clinical trials and AMG510 (sotorasib) has been approved for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer. However, the overall responsive rate of KRasG12C inhibitors was around 50% in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable. It is of great importance to discover biomarkers to distinguish patients who are likely benefitted. Moreover, adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies. Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRasG12C inhibitors in preclinical settings. This review summarized the recent progress of covalent KRasG12C inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.

Keywords

BiomarkersDrug resistanceCovalent KRasG12CinhibitorsHuman cancersKRASG12Cmutation

References

1

Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE. 2004;2004(250):RE13.
Crossref Google Scholar
2

Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459-465.
Crossref Google Scholar
3

Khan I, Rhett JM, O’Bryan JP. Therapeutic targeting of RAS: new hope for drugging the "undruggable". Biochim Biophys Acta Mol Cell Res. 2020;1867(2):118570.
Crossref Google Scholar
4

Liu P, Wang Y, Li X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm Sin B. 2019;9(5):871-879.
Crossref Google Scholar
5

Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129(5):865-877.
Crossref Google Scholar
6

Nagasaka M, Li Y, Sukari A, et al. KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat Rev. 2020;84: 101974.
Crossref Google Scholar
7

Banno K, Yanokura M, Iida M, et al. Carcinogenic mechanisms of endometrial cancer: involvement of genetics and epigenetics. J Obstet Gynaecol Res. 2014;40(8):1957-1967.
Crossref Google Scholar
8

Lu S, Jang H, Gu S, et al. Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view. Chem Soc Rev. 2016;45(18):4929-4952.
Crossref Google Scholar
9

Koera K, Nakamura K, Nakao K, et al. K-Ras is essential for the development of the mouse embryo. Oncogene. 1997;15(10):1151-1159.
Crossref Google Scholar
10

Nakamura K, Ichise H, Nakao K, et al. Partial functional overlap of the three ras genes in mouse embryonic development. Oncogene. 2008;27(21):2961-2968.
Crossref Google Scholar
11

Potenza N, Vecchione C, Notte A, et al. Replacement of K-Ras with H-Ras supports normal embryonic development despite inducing cardiovascular pathology in adult mice. EMBO Rep. 2005;6(5):432-437.
Crossref Google Scholar
12

Wilson CY, Tolias P. Recent advances in cancer drug discovery targeting RAS. Drug Discov Today. 2016;21(12):1915-1919.
Crossref Google Scholar
13

Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399-405.
Crossref Google Scholar
14

Neumann J, Zeindl-Eberhart E, Kirchner T, et al. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205(12):858-862.
Crossref Google Scholar
15

Lanman BA, Allen JR, Allen JG, et al. Discovery of a covalent inhibitor of KRAS G12C (AMG 510) for the treatment of solid tumors. J Med Chem. 2019;63(1):52-65.
Crossref Google Scholar
16

Rodenhuis S. Ras and human tumors. Semin Cancer Biol. 1992; 3(4):241-247.
Google Scholar
17

Croce CM. Oncogenes and cancer. N Engl J Med. 2008;358(5):502-511.
Crossref Google Scholar
18

Khosravi-Far R, Der CJ. The Ras signal transduction pathway. Cancer Metastasis Rev. 1994;13(1):67-89.
Crossref Google Scholar
19

Hansen R, Peters U, Babbar A, et al. The reactivity-driven biochemical mechanism of covalent KRAS G12C inhibitors. Nat Struct Mol Biol. 2018;25(6):454-462.
Crossref Google Scholar
20

Balmain A, Pragnell IB. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature. 1983;303(5912):72-74.
Crossref Google Scholar
21

Sukumar S, Notario V, Martin-Zanca D, et al. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations. Nature. 1983;306(5944):658-661.
Crossref Google Scholar
22

Guerrero I, Calzada P, Mayer A, et al. A molecular approach to leukemogenesis: mouse lymphomas contain an activated c-ras oncogene. Proc Natl Acad Sci U S A. 1984;81(1):202-205.
Crossref Google Scholar
23

Lim KH, Counter CM. Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell. 2005;8(5):381-392.
Crossref Google Scholar
24

Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell. 2002;2(3):243-247.
Crossref Google Scholar
25

Ji H, Ramsey MR, Hayes DN, et al. LKB1 modulates lung cancer differentiation and metastasis. Nature. 2007; 448(7155):807-810.
Crossref Google Scholar
26

Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7(5):469-483.
Crossref Google Scholar
27

Haigis KM, Kendall KR, Wang Y, et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 2008;40(5):600-608.
Crossref Google Scholar
28
Chen WC, To MD, Westcott PMK, et al. Regulation of KRAS4A/B splicing in cancer stem cells by the RBM39 splicing complex. bioRxiv. 2019; Preprint at https://doi.org/10.1101/646125.
Crossref
29

Ryan MB, Corcoran RB. Therapeutic strategies to target RAS-mutant cancers. Nat Rev Clin Oncol. 2018;15(11):709-720.
Crossref Google Scholar
30

van Maldegem F, Downward J. Mutant KRAS at the heart of tumor immune evasion. Immunity. 2020;52(1):14-16.
Crossref Google Scholar
31

Cox AD, Fesik SW, Kimmelman AC, et al. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014; 13(11):828-851.
Crossref Google Scholar
32

Gibbs JB, Graham SL, Hartman GD, et al. Farnesyltransferase inhibitors versus Ras inhibitors. Curr Opin Chem Biol. 1997; 1(2):197-203.
Crossref Google Scholar
33

Sanclemente M, Francoz S, Esteban-Burgos L, et al. c-RAF ablation induces regression of advanced Kras/Trp53 mutant lung adenocarcinomas by a mechanism independent of MAPK signaling. Cancer Cell. 2018;33(2):217-228.
Crossref Google Scholar
34

Jones GG, Del Río IB, Sari S, et al. SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers. Nat Commun. 2019;10(1):2532.
Crossref Google Scholar
35

Blasco MT, Navas C, Martín-Serrano G, et al. Complete regression of advanced pancreatic ductal adenocarcinomas upon combined inhibition of EGFR and C-RAF. Cancer Cell. 2019;35(4):573-587.
Crossref Google Scholar
36

Luo J, Emanuele MJ, Li D, et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell. 2009;137(5):835-848.
Crossref Google Scholar
37

te Heesen H, Gerwert K, Schlitter J. Role of the arginine finger in Ras.RasGAP revealed by QM/MM calculations. FEBS Lett. 2007;581(29):5677-5684.
Crossref Google Scholar
38

Hatakeyama K, Harada T, Kagamiyama H. IMP dehydrogenase inhibitors reduce intracellular tetrahydrobiopterin levels through reduction of intracellular GTP levels. Indications of the regulation of GTP cyclohydrolase I activity by restriction of GTP availability in the cells. J Biol Chem. 1992;267(29):20734-20739.
Crossref Google Scholar
39

Nickerson S, Joy ST, Arora PS, et al. An orthosteric inhibitor of the RAS-SOS interaction. Enzymes. 2013;34(Pt. B):25-39.
Crossref Google Scholar
40

Shima F, Yoshikawa Y, Ye M, et al. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proc Natl Acad Sci U S A. 2013;110(20):8182-8187.
Crossref Google Scholar
41

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):316-329.
Crossref Google Scholar
42

Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019; 575(7781):217-223.
Crossref Google Scholar
43

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.
Crossref Google Scholar
44

Misale S, Fatherree JP, Cortez E, et al. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin Cancer Res. 2019;25(2):796-807.
Crossref Google Scholar
45

Ni D, Li X, He X, et al. Drugging K-Ras(G12C) through covalent inhibitors: mission possible? Pharmacol Ther. 2019;202: 1-17.
Crossref Google Scholar
46

Molina-Arcas M, Moore C, Rana S, et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019;11(510):eaaw7999.
Crossref Google Scholar
47

Govindan R, Fakih MG, Price TJ, et al. Phase 1 trial evaluating safety, efficacy, and PK of AMG 510, a novel KRASG12C inhibitor, in non-small cell lung cancer. J Thorac Oncol. 2019;14(11):S1191-S1192.
Crossref Google Scholar
48
Janne PA, Papadopoulous K, Ou SI, et al. A Phase 1 clinical trial evaluating the pharmacokinetics (PK), safety, and clinical activity of MRTX849, a mutant-selective small molecule KRAS G12C inhibitor, in advanced solid tumors. International Conference on Molecular Targets and Cancer Therapeutics. 2019;October 26-30.
49

Hata AN, Shaw AT. Resistance looms for KRAS(G12C) inhibitors. Nat Med. 2020;26(2):169-170.
Crossref Google Scholar
50

Awad MM, Liu S, Rybkin Ⅱ, et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N Engl J Med. 2021;384(25):2382-2393.
Crossref Google Scholar
51

Downward J. RAS synthetic lethal screens revisited: still seeking the elusive prize? Clin Cancer Res. 2015;21(8):1802-1809.
Crossref Google Scholar
52

Ostrem JM, Peters U, Sos ML, et al. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548-551.
Crossref Google Scholar
53
Newswire P. Amgen Announces New Clinical Data Evaluating Novel Investigational KRAS(G12C) Inhibitor in Larger Patient Group at WCLC 2019; 2019. https://www.amgen.com/.
54

Lito P, Solomon M, Li LS, et al. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604-608.
Crossref Google Scholar
55

Hobbs GA, Wittinghofer A, Der CJ. Selective targeting of the KRAS G12C mutant: kicking KRAS when it’s down. Cancer Cell. 2016;29(3):251-253.
Crossref Google Scholar
56

Janes MR, Zhang J, Li LS, et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell. 2018;172(3):578-589.
Crossref Google Scholar
57

Jiao D, Yang S. Overcoming resistance to drugs targeting KRAS(G12C) mutation. Innovation. 2020;1(2):100035.
Crossref Google Scholar
58

Rex K, Saiki AY, Sun JR, et al. In vivo characterization of AMG 510-a potent and selective KRASG12C covalent small molecule inhibitor in preclinical KRASG12C cancer models. Cancer Res. 2019;79(13 Supplement):3090.
Crossref Google Scholar
59

Hong DS, Fakih MG, Strickler JH, et al. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207-1217.
Crossref Google Scholar
60
FDA Approves LUMAKRASTM (Sotorasib), the First and Only Targeted Treatment for Patients with KRAS G12C-Mutated Locally Advanced or Metastatic Non-small Cell Lung Cancer; 2021. https://www.amgen.com/newsroom/press-releases/2021/05/fda-approves-lumakras-sotorasib-the-first-and-onlytargeted-treatment-for-patients-with-kras-g12cmutatedlocally-advanced-or-metastatic-nonsmall-cell-lung-cancer.
61

Christensen JG, Olson P, Briere T, et al. Targeting Kras(g12c)-mutant cancer with a mutation-specific inhibitor. J Intern Med. 2020;288(2):183-191.
Crossref Google Scholar
62

Jänne PA, Rybkin Ⅱ, Spira AI, et al. Activity and safety of adagrasib (MRTX849) in advanced/metastatic non-small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. Eur J Canc. 2020;138(S2):S1-S2.
Crossref Google Scholar
63

Johnson ML, Ou SHI, Barve M, et al. Activity and safety of adagrasib (MRTX849) in patients with colorectal cancer (CRC) and other solid tumors harboring a KRAS G12C mutation. Eur J Canc. 2020;138(S2):S2.
Crossref Google Scholar
64
Mirati Therapeutics Reports Investigational Adagrasib (MRTX849) Preliminary Data Demonstrating Tolerability and Durable Anti-tumor Activity as Well as Initial MRTX1133 Preclinical Data; 2020. https://ir.mirati.com/news-releases/news-details/2020/Mirati-Therapeutics-Reports-Investigational-Adagrasib-MRTX849-Preliminary-Data-Demonstrating-Tolerability-and-Durable-Anti-Tumor-Activity-as-wellas-Initial-MRTX1133-Preclinical-Data/default.aspx.
65

McCormick F. Progress in targeting RAS with small molecule drugs. Biochem J. 2019;476(2):365-374.
Crossref Google Scholar
66

Klempner SJ, Hata AN. Can the help match the hype? KRAS(G12C)-specific inhibitors and beyond. Cancer Discov. 2020;10(1):20-22.
Crossref Google Scholar
67

Amodio V, Yaeger R, Arcella P, et al. EGFR blockade reverts resistance to KRAS(G12C) inhibition in colorectal cancer. Cancer Discov. 2020;10(8):1129-1139.
Crossref Google Scholar
68

Ryan MB, Fece de la Cruz F, Phat S, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition. Clin Canc Res. 2020;26(7):1633-1643.
Crossref Google Scholar
69

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):5962-5973.
Crossref Google Scholar
70
Results from Phase 2 CodeBreaK 100 Show LUMAKRASTM (Sotorasib) Is the First and Only KRAS G12C Inhibitor with Overall Survival Data; 2021. https://www.amgen.com/newsroom/press-releases/2021/06/results-from-phase-2-codebreak-100-show-lumakras-sotorasib-is-the-first-and-onlykras-g12c-inhibitor-with-overall-survival-data.
71

Kelsey I, Manning BD. mTORC1 status dictates tumor response to targeted therapeutics. Sci Signal. 2013;6(294):pe31.
Crossref Google Scholar
72

Bunda S, Burrell K, Heir P, et al. Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis. Nat Commun. 2015;6:e8859.
Crossref Google Scholar
73

Fedele C, Li S, Teng KW, et al. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med. 2021;218(1):e20201414.
Crossref Google Scholar
74

Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(1):103-119.
Crossref Google Scholar
75

Seger R, Krebs EG. The MAPK signaling cascade. Faseb J. 1995; 9(9):726-735.
Crossref Google Scholar
76

Costa-Cabral S, Brough R, Konde A, et al. CDK1 is a synthetic lethal target for KRAS mutant tumours. PloS One. 2016;11(2):e0149099.
Crossref Google Scholar
77

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.
Crossref Google Scholar
78

Santana-Codina N, Chandhoke AS, Yu Q, et al. Defining and targeting adaptations to oncogenic KRAS(G12C) inhibition using quantitative temporal proteomics. Cell Rep. 2020;30(13):4584-4599.
Crossref Google Scholar
79

Xue JY, Zhao Y, Aronowitz J, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature. 2020;577(7790):421-425.
Crossref Google Scholar
80

Bishop L, Chen Z, Omar O, et al. Targeting Aurka effectively suppresses Kras-mutant tumorigenesis through regulating P70S6K phosphorylaton in gastrointestinal cancers. Gastroenterology. 2017;152(5):S41.
Crossref Google Scholar
81

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):1913-1922.
Crossref Google Scholar
82

Welsch ME, Kaplan A, Chambers JM, et al. Multivalent small-molecule pan-RAS inhibitors. Cell. 2017;168(5):878-889.
Crossref Google Scholar
83

Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-196.
Crossref Google Scholar
84

Fischer KR, Durrans A, Lee S, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527(7579):472-476.
Crossref Google Scholar
85

Chen N, Fang W, Lin Z, et al. KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma. Cancer Immunol Immunother. 2017;66(9):1175-1187.
Crossref Google Scholar
86

Weijzen S, Velders MP, Kast WM. Modulation of the immune response and tumor growth by activated Ras. Leukemia. 1999; 13(4):502-513.
Crossref Google Scholar
87

Goebel L, Müller MP, Goody RS, et al. KRasG12C inhibitors in clinical trials: a short historical perspective. RSC Med Chem. 2020;11(7):760-770.
Crossref Google Scholar
Genes & Diseases
Volume 10 Issue 2,
March 2023
Pages 403-414
DOI: 10.1016/j.gendis.2021.08.011
Cite this article:
Li H-y, Qi W-l, Wang Y-x, et al. Covalent inhibitor targets KRasG12C: A new paradigm for drugging the undruggable and challenges ahead. Genes & Diseases, 2023, 10(2): 403-414. https://doi.org/10.1016/j.gendis.2021.08.011

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Received: 06 July 2021
Revised: 12 August 2021
Accepted: 27 August 2021
Published: 28 September 2021
© 2021 The Authors.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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