Synapse - Diverse alterations associated with resistance to KRAS(G12C) inhibition

Diverse alterations associated with resistance to KRAS(G12C) inhibition Journal Article

Authors:	Zhao, Y.; Murciano-Goroff, Y. R.; Xue, J. Y.; Ang, A.; Lucas, J.; Mai, T. T.; Da Cruz Paula, A. F.; Saiki, A. Y.; Mohn, D.; Achanta, P.; Sisk, A. E.; Arora, K. S.; Roy, R. S.; Kim, D.; Li, C.; Lim, L. P.; Li, M.; Bahr, A.; Loomis, B. R.; de Stanchina, E.; Reis-Filho, J. S.; Weigelt, B.; Berger, M.; Riely, G.; Arbour, K. C.; Lipford, J. R.; Li, B. T.; Lito, P.
Article Title:	Diverse alterations associated with resistance to KRAS(G12C) inhibition
Abstract:	Inactive state-selective KRAS(G12C) inhibitors1–8 demonstrate a 30–40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords:	allele; inhibitor; inhibition; cell; disease resistance; cell component; nutation
Journal Title:	Nature
Volume:	599
Issue:	7886
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2021-11-25
Start Page:	679
End Page:	683
Language:	English
DOI:	10.1038/s41586-021-04065-2
PROVIDER:	scopus
PUBMED:	34759319
PMCID:	PMC8887821
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85118884434&doi=10.1038%2fs41586-021-04065-2&partnerID=40&md5=21c9ec34827c3c8d28ec88fb5b5aa197
Notes:	Article -- Export Date: 3 January 2022 -- Source: Scopus