Diverse alterations associated with resistance to KRAS(G12C) inhibition

Yulei Zhao, Yonina R. Murciano-Goroff, Jenny Y. Xue, Agnes Ang, Jessica Lucas, Trang T. Mai, Arnaud F. Cruz Paula, Anne Y. Saiki, Deanna Mohn, Pragathi Achanta, Ann E. Sisk, Kanika S. Arora, Rohan S. Roy, Dongsung Kim, Chuanchuan Li, Lee P. Lim, Mark Li, Amber Bahr, Brian R. Loomis, Elisa Stanchina, Jorge S. Reis-Filho, Britta Weigelt, Michael Berger, Gregory Riely, Kathryn C. Arbour, J. Russell Lipford, Bob T. Li and Piro Lito ()
Additional contact information
Yulei Zhao: Memorial Sloan Kettering Cancer
Yonina R. Murciano-Goroff: Memorial Sloan Kettering Cancer Center
Jenny Y. Xue: Memorial Sloan Kettering Cancer
Agnes Ang: Amgen
Jessica Lucas: Memorial Sloan Kettering Cancer
Trang T. Mai: Memorial Sloan Kettering Cancer
Arnaud F. Cruz Paula: Memorial Sloan Kettering Cancer Center
Anne Y. Saiki: Amgen
Deanna Mohn: Amgen
Pragathi Achanta: Amgen
Ann E. Sisk: Memorial Sloan Kettering Cancer Center
Kanika S. Arora: Memorial Sloan Kettering Cancer Center
Rohan S. Roy: Weill Cornell–Rockefeller–Sloan Kettering Tri-Institutional MD-PhD Program
Dongsung Kim: Memorial Sloan Kettering Cancer
Chuanchuan Li: Memorial Sloan Kettering Cancer
Lee P. Lim: Resolution Bioscience
Mark Li: Resolution Bioscience
Amber Bahr: Memorial Sloan Kettering Cancer Center
Brian R. Loomis: Memorial Sloan Kettering Cancer Center
Elisa Stanchina: Memorial Sloan Kettering Cancer Center
Jorge S. Reis-Filho: Memorial Sloan Kettering Cancer Center
Britta Weigelt: Memorial Sloan Kettering Cancer Center
Michael Berger: Memorial Sloan Kettering Cancer Center
Gregory Riely: Memorial Sloan Kettering Cancer Center
Kathryn C. Arbour: Memorial Sloan Kettering Cancer Center
J. Russell Lipford: Amgen
Bob T. Li: Memorial Sloan Kettering Cancer Center
Piro Lito: Memorial Sloan Kettering Cancer

Nature, 2021, vol. 599, issue 7886, 679-683

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-04065-2

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