Reference Detail

Ref Type

Journal Article

PMID

(33824136)

Authors

Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, Michel AG, Syed MU, Fella KA, Sakhi M, Baiev I, Juric D, Gainor JF, Klempner SJ, Lennerz JK, Siravegna G, Bar-Peled L, Hata AN, Heist RS, Corcoran RB

Title

Clinical Acquired Resistance to KRAS G12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	11	8	2021 Aug	1913-1922	Cancer Discov

URL

Abstract Text

Mutant-selective KRAS G12C inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in KRASG12C -mutant cancers, including non-small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRAS G12C inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a patient with KRASG12C NSCLC who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes ( KRAS, NRAS, BRAF, MAP2K1 ), all of which converge to reactivate RAS-MAPK signaling. Notably, a novel KRASY96D mutation affecting the switch-II pocket, to which MRTX849 and other inactive-state inhibitors bind, was identified that interferes with key protein-drug interactions and confers resistance to these inhibitors in engineered and patient-derived KRASG12C cancer models. Interestingly, a novel, functionally distinct tricomplex KRAS G12C active-state inhibitor RM-018 retained the ability to bind and inhibit KRAS G12C/Y96D and could overcome resistance. SIGNIFICANCE: In one of the first reports of clinical acquired resistance to KRAS G12C inhibitors, our data suggest polyclonal RAS-MAPK reactivation as a central resistance mechanism. We also identify a novel KRAS switch-II pocket mutation that impairs binding and drives resistance to inactive-state inhibitors but is surmountable by a functionally distinct KRAS G12C inhibitor. See related commentary by Pinnelli and Trusolino, p. 1874 . This article is highlighted in the In This Issue feature, p. 1861 .

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
RM-018	RM-018	3	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
RM-018		RM018\|RM 018	KRAS G12C inhibitor 34	RM-018 covalently binds and inhibits GTP-bound KRAS G12C by forming a complex with the chaperone protein cyclophilin A, resulting in decreased downstream signaling and potentially inhibiting tumor growth (PMID: 33824136).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	no benefit	RM-018	Preclinical - Cell culture	Actionable	In a preclinical study, RM-018 did not inhibit growth of melanoma cells harboring BRAF V600E in culture (PMID: 33824136).	33824136