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Annual Review of Cancer Biology

Volume 6, 2022

Targeting KRAS G12C with Covalent Inhibitors

Abstract

is the most frequently mutated oncogene in cancer. Following numerous attempts to inhibit KRAS spanning multiple decades, recent efforts aimed at covalently targeting the mutant cysteine of KRAS G12C have yielded very encouraging results. Indeed, one such molecule, sotorasib, has already received accelerated US Food and Drug Administration approval with phase III clinical trials currently underway. A second molecule, adagrasib, has also progressed to phase III, and several others have entered early-phase clinical trials. The success of these efforts has inspired an array of novel approaches targeting KRAS, with some reporting extension to the two most common oncogenic KRAS mutations, G12V and G12D.

Keyword(s): colorectal cancer, KRAS G12C, lung cancer, mutant-specific
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/content/journals/10.1146/annurev-cancerbio-041621-012549
2022-04-11
2024-05-02
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Literature Cited

  1. Adachi Y, Ito K, Hayashi Y, Kimura R, Tan TZ et al. 2020. 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. 26:5962–73
     [Google Scholar]
  2. Ahmed TA, Adamopoulos C, Karoulia Z, Wu X, Sachidanandam R et al. 2019. SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors. Cell Rep. 26:65–78.e5
     [Google Scholar]
  3. Aime A, Coulet F, Lefevre JH, Colas C, Cervera P et al. 2015. Somatic c.34G>T KRAS mutation: a new prescreening test for MUTYH-associated polyposis?. Cancer Genet. 208:390–95
     [Google Scholar]
  4. Akslen LA, Puntervoll H, Bachmann IM, Straume O, Vuhahula E et al. 2008. Mutation analysis of the EGFR-NRAS-BRAF pathway in melanomas from black Africans and other subgroups of cutaneous melanoma. Melanoma Res. 18:29–35
     [Google Scholar]
  5. Amodio V, Yaeger R, Arcella P, Cancelliere C, Lamba S et al. 2020. EGFR blockade reverts resistance to KRASG12C inhibition in colorectal cancer. Cancer Discov. 10:1129–39
     [Google Scholar]
  6. André T, Shiu K-K, Kim TW, Jensen BV, Jensen LH et al. 2020. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N. Engl. J. Med. 383:2207–18
     [Google Scholar]
  7. Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. 1998. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J. Natl. Cancer Inst. 90:675–84
     [Google Scholar]
  8. Arbour KC, Jordan E, Kim HR, Dienstag J, Yu HA et al. 2018. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non–small cell lung cancer. Clin. Cancer Res. 24:334–40
     [Google Scholar]
  9. Aronheim A, Engelberg D, Li N, Al-Alawi N, Schlessinger J, Karin M 1994. Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway. Cell 78:949–61
     [Google Scholar]
  10. Auewarakul CU, Lauhakirti D, Tocharoentanaphol C 2006. Frequency of RAS gene mutation and its cooperative genetic events in Southeast Asian adult acute myeloid leukemia. Eur. J. Haematol. 77:51–56
     [Google Scholar]
  11. Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J et al. 2021. Acquired resistance to KRASG12C inhibition in cancer. N. Engl. J. Med. 384:2382–93
     [Google Scholar]
  12. Belchis DA, Tseng L-H, Gniadek T, Haley L, Lokhandwala P et al. 2016. Heterogeneity of resistance mutations detectable by next-generation sequencing in TKI-treated lung adenocarcinoma. Oncotarget 7:45237–48
     [Google Scholar]
  13. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB et al. 2012. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491:399–405
     [Google Scholar]
  14. Boch C, Kollmeier J, Roth A, Stephan-Falkenau S, Misch D et al. 2013. The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study. BMJ Open 3:e002560
     [Google Scholar]
  15. Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G et al. 2011. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann. Oncol. 22:1535–46
     [Google Scholar]
  16. Bond MJ, Chu L, Nalawansha DA, Li K, Crews CM 2020. Targeted degradation of oncogenic KRASG12C by VHL-recruiting PROTACs. ACS Cent. Sci. 6:1367–75
     [Google Scholar]
  17. Bowen DT, Frew ME, Hills R, Gale RE, Wheatley K et al. 2005. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood 106:2113–19
     [Google Scholar]
  18. Buttitta F, Barassi F, Fresu G, Felicioni L, Chella A et al. 2006. Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: Mutations are mainly present in adenocarcinomas with bronchioloalveolar features. Int. J. Cancer 119:2586–91
     [Google Scholar]
  19. Canon J, Rex K, Saiki AY, Mohr C, Cooke K et al. 2019. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575:217–23
     [Google Scholar]
  20. Casey PJ, Solski PA, Der CJ, Buss JE. 1989. p21ras is modified by a farnesyl isoprenoid. PNAS 86:8323–27
     [Google Scholar]
  21. Challen C, Guo K, Collier JD, Cavanagh D, Bassendine MF. 1992. Infrequent point mutations in codons 12 and 61 of ras oncogenes in human hepatocellular carcinomas. J. Hepatol. 14:342–46
     [Google Scholar]
  22. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M et al. 2012. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF-mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2:227–35
     [Google Scholar]
  23. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ et al. 2005. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353:2135–47
     [Google Scholar]
  24. De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D et al. 2010. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304:1812–20
     [Google Scholar]
  25. Downward J. 2003. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3:11–22
     [Google Scholar]
  26. El-Jawhari JJ, El-Sherbiny YM, Scott GB, Morgan RS, Prestwich R et al. 2014. Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes. Mol. Immunol. 58:160–68
     [Google Scholar]
  27. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR et al. 2008. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14:1351–56
     [Google Scholar]
  28. Fedele C, Li S, Teng KW, Foster CJR, Peng D et al. 2021. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J. Exp. Med. 218:e20201414
     [Google Scholar]
  29. Finn SP, Addeo A, Dafni U, Thunnissen E, Bubendorf L et al. 2021. Prognostic impact of KRAS G12C mutation in patients with NSCLC: results from the ETOP Lungscape Project. J. Thorac. Oncol. 16:990–1002
     [Google Scholar]
  30. Frech M, Darden TA, Pedersen LG, Foley CK, Charifson PS et al. 1994. Role of glutamine-61 in the hydrolysis of GTP by p21H-ras: an experimental and theoretical study. Biochemistry 33:3237–44
     [Google Scholar]
  31. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E et al. 2018. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378:2078–92
     [Google Scholar]
  32. Garon EB, Ciuleanu T-E, Arrieta O, Prabhash K, Syrigos KN et al. 2014. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384:665–73
     [Google Scholar]
  33. Gentile DR, Rathinaswamy MK, Jenkins ML, Moss SM, Siempelkamp BD et al. 2017. Ras binder induces a modified switch-II pocket in GTP and GDP states. Cell Chem. Biol. 24:1455–66.e14
     [Google Scholar]
  34. Gerlach D, Gmachl M, Ramharter J, Teh J, Fu S-C et al. 2020. BI-3406 and BI 1701963: Potent and selective SOS1::KRAS inhibitors induce regressions in combination with MEK inhibitors or irinotecan. Cancer Res 80:1091 Abstr. )
     [Google Scholar]
  35. Goldman JW, Mazieres J, Barlesi F, Koczywas M, Dragnev KH et al. 2018. A randomized phase 3 study of abemaciclib versus erlotinib in previously treated patients with stage IV NSCLC with KRAS mutation: JUNIPER. J. Clin. Oncol. 36:9025
     [Google Scholar]
  36. Guan JL, Zhong WZ, An SJ, Yang JJ, Su J et al. 2013. KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy. Ann. Surg. Oncol. 20:1381–88
     [Google Scholar]
  37. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R et al. 2020. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10:54–71
     [Google Scholar]
  38. He XP, Song FJ, Liu XY, Wang Z, Li XX et al. 2013. The relationship between KRAS gene mutations and HLA class I antigen downregulation in the metastasis of non-small cell lung cancer. J. Int. Med. Res. 41:1473–83
     [Google Scholar]
  39. Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A et al. 2019. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction. PNAS 116:2551–60
     [Google Scholar]
  40. Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D et al. 2021. BI-3406, a potent and selective SOS1–KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov 11:142–57
     [Google Scholar]
  41. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA et al. 2020. KRASG12C inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383:1207–17
     [Google Scholar]
  42. Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD 2015. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol. Cancer Res. 13:1325–35
     [Google Scholar]
  43. Janes MR, Zhang J, Li LS, Hansen R, Peters U et al. 2018. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172:578–89.e17
     [Google Scholar]
  44. Jänne PA, Rybkin II, Spira AI, Riely GJ, Papadopoulos KP et al. 2020. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. Eur. J. Cancer 138:S1–2
     [Google Scholar]
  45. Jeanson A, Tomasini P, Souquet-Bressand M, Brandone N, Boucekine M et al. 2019. Efficacy of immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer (NSCLC). J. Thorac. Oncol. 14:1095–101
     [Google Scholar]
  46. John J, Frech M, Wittinghofer A. 1988. Biochemical properties of Ha-ras encoded p21 mutants and mechanism of the autophosphorylation reaction. J. Biol. Chem. 263:11792–99
     [Google Scholar]
  47. Jones RP, Sutton PA, Evans JP, Clifford R, McAvoy A et al. 2017. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br. J. Cancer 116:923–29
     [Google Scholar]
  48. Jones S, Lambert S, Williams GT, Best JM, Sampson JR, Cheadle JP 2004. Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas. Br. J. Cancer 90:1591–93
     [Google Scholar]
  49. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D et al. 2008. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359:1757–65
     [Google Scholar]
  50. Kim JH, Kim HS, Kim BJ 2017. Prognostic value of KRAS mutation in advanced non-small-cell lung cancer treated with immune checkpoint inhibitors: a meta-analysis and review. Oncotarget 8:2948248–52
     [Google Scholar]
  51. Klaeger S, Heinzlmeir S, Wilhelm M, Polzer H, Vick B et al. 2017. The target landscape of clinical kinase drugs. Science 358:eaan4368
     [Google Scholar]
  52. Kodaz H. 2017. Frequency of RAS Mutations (KRAS, NRAS, HRAS) in human solid cancer. Eurasian J. Med. Oncol. 1:11–7
     [Google Scholar]
  53. Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ et al. 2015. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J. Clin. Oncol. 33:4032–38
     [Google Scholar]
  54. Lee JH, Choi JW, Kim YS. 2011. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br. J. Dermatol. 164:776–84
     [Google Scholar]
  55. Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B et al. 2006. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66:3992–95
     [Google Scholar]
  56. Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E et al. 2012. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22:668–82
     [Google Scholar]
  57. Lito P, Solomon M, Li L-S, Hansen R, Rosen N. 2016. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 351:604–8
     [Google Scholar]
  58. Liu C, Lu H, Wang H, Loo A, Zhang X et al. 2021. Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin. Cancer Res. 27:342–54
     [Google Scholar]
  59. Lou K, Steri V, Ge AY, Hwang YC, Yogodzinski CH et al. 2019. KRASG12C inhibition produces a driver-limited state revealing collateral dependencies. Sci. Signal. 12:eaaw9450
     [Google Scholar]
  60. Misale S, Fatherree JP, Cortez E, Li C, Bilton S et al. 2019. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin. Cancer Res. 25:796–807
     [Google Scholar]
  61. Molina-Arcas M, Moore C, Rana S, van Maldegem F, Mugarza E et al. 2019. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci. Transl. Med. 11:eaaw7999
     [Google Scholar]
  62. Nassar AH, Adib E, Kwiatkowski DJ 2021. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N. Engl. J. Med. 384:185–87
     [Google Scholar]
  63. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. 2009. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol. Res. Pract. 205:858–62
     [Google Scholar]
  64. Oddo D, Sennott EM, Barault L, Valtorta E, Arena S et al. 2016. Molecular landscape of acquired resistance to targeted therapy combinations in BRAF-mutant colorectal cancer. Cancer Res. 76:4504–15
     [Google Scholar]
  65. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. 2013. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548–51
     [Google Scholar]
  66. Patricelli MP, Janes MR, Li LS, Hansen R, Peters U et al. 2016. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 6:316–29
     [Google Scholar]
  67. Puyol M, Martin A, Dubus P, Mulero F, Pizcueta P et al. 2010. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18:63–73
     [Google Scholar]
  68. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csoszi T et al. 2016. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375:1823–33
     [Google Scholar]
  69. Reinersman JM, Johnson ML, Riely GJ, Chitale DA, Nicastri AD et al. 2011. Frequency of EGFR and KRAS mutations in lung adenocarcinomas in African Americans. J. Thorac. Oncol. 6:28–31
     [Google Scholar]
  70. Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A et al. 2008. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin. Cancer Res. 14:5731–34
     [Google Scholar]
  71. Rodenhuis S, van de Wetering ML, Mooi WJ, Evers SG, van Zandwijk N, Bos JL. 1987. Mutational activation of the K-ras oncogene. N. Engl. J. Med. 317:929–35
     [Google Scholar]
  72. Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E et al. 2020. Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition. Clin. Cancer Res. 26:1633–43
     [Google Scholar]
  73. Santana-Codina N, Chandhoke AS, Yu Q, Malachowska B, Kuljanin M et al. 2020. Defining and targeting adaptations to oncogenic KRASG12C inhibition using quantitative temporal proteomics. Cell Rep. 30:4584–99.e4
     [Google Scholar]
  74. Schabath MB, Welsh EA, Fulp WJ, Chen L, Teer JK et al. 2016. Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. Oncogene 35:3209–16
     [Google Scholar]
  75. Scheffzek K, Ahmadian MR, Kabsch W, Wiesmüller L, Lautwein A et al. 1997. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277:333–38
     [Google Scholar]
  76. Schmid K, Oehl N, Wrba F, Pirker R, Pirker C, Filipits M. 2009. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin. Cancer Res. 15:4554–60
     [Google Scholar]
  77. Sebastian M, Eberhardt WEE, Hoffknecht P, Metzenmacher M, Wehler T et al. 2021. KRAS G12C-mutated advanced non-small cell lung cancer: a real-world cohort from the German prospective, observational, nation-wide CRISP registry (AIO-TRK-0315). Lung Cancer 154:51–61
     [Google Scholar]
  78. Sergina NV, Rausch M, Wang D, Blair J, Hann B et al. 2007. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445:437–41
     [Google Scholar]
  79. Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM et al. 2018. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8:822–35
     [Google Scholar]
  80. Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS et al. 2021. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med. 384:2371–81
     [Google Scholar]
  81. Smith MJ, Neel BG, Ikura M. 2013. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. PNAS 110:4574–79
     [Google Scholar]
  82. Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM et al. 2009. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. PNAS 106:18351–56
     [Google Scholar]
  83. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC et al. 2012. Survival in BRAF V600–mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 366:707–14
     [Google Scholar]
  84. Staudacher JJ, Yazici C, Bul V, Zeidan J, Khalid A et al. 2017. Increased frequency of KRAS mutations in African Americans compared with Caucasians in sporadic colorectal cancer. Clin. Transl. Gastroenterol. 8:e124
     [Google Scholar]
  85. Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J et al. 2021. Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS–MAPK reactivation. Cancer Discov 11:81913–22
     [Google Scholar]
  86. Tejpar S, Celik I, Schlichting M, Sartorius U, Bokemeyer C, Van Cutsem E. 2012. Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J. Clin. Oncol. 30:3570–77
     [Google Scholar]
  87. Trahey M, McCormick F. 1987. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238:542–45
     [Google Scholar]
  88. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM et al. 2017. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547:453–57
     [Google Scholar]
  89. Wang X, Ricciuti B, Nguyen T, Li X, Rabin MS et al. 2021. Association between smoking history and tumor mutation burden in advanced non-small cell lung cancer. Cancer Res 81:92566–73
     [Google Scholar]
  90. Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M et al. 2009. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 69:4286–93
     [Google Scholar]
  91. Xu GF, O'Connell P, Viskochil D, Cawthon R, Robertson M et al. 1990. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608
     [Google Scholar]
  92. Xu W, Yang Z, Lu N 2015. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh. Migr. 9:317–24
     [Google Scholar]
  93. Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A et al. 2020. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 577:421–25
     [Google Scholar]
  94. Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M et al. 2020. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 581:100–5
     [Google Scholar]
  95. Zeng M, Lu J, Li L, Feru F, Quan C et al. 2017. Potent and selective covalent quinazoline inhibitors of KRAS G12C. Cell Chem. Biol. 24:1005–16.e3
     [Google Scholar]
  96. Zeng M, Xiong Y, Safaee N, Nowak RP, Donovan KA et al. 2020. Exploring targeted degradation strategy for oncogenic KRASG12C. Cell Chem. Biol. 27:19–31.e6
     [Google Scholar]
  97. Zhang Z, Shokat KM. 2019. Bifunctional small-molecule ligands of K-Ras induce its association with immunophilin proteins. Angew. Chem. Int. Ed. Engl. 58:16314–19
     [Google Scholar]
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Targeting KRAS G12C with Covalent Inhibitors
Annual Review of Cancer Biology 6, 49 (2022); https://doi.org/10.1146/annurev-cancerbio-041621-012549
/content/journals/10.1146/annurev-cancerbio-041621-012549
/content/journals/10.1146/annurev-cancerbio-041621-012549
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