Diverse alterations associated with resistance to KRAS(G12C) inhibition
Inactive state-selective KRAS(G12C) inhibitors 1 – 8 demonstrate a 30–40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer 9 . The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation....
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| Published in: | Nature (London) Vol. 599; no. 7886; pp. 679 - 683 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
25-11-2021
Nature Publishing Group |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Inactive state-selective KRAS(G12C) inhibitors
1
–
8
demonstrate a 30–40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer
9
. 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.
Multiple treatment-emergent alterations appear in patients with advanced-stage cancer who were treated with a KRAS inhibitor. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. These authors jointly supervised this work. Y.Z., Y.R.M.G., J.Y.X., A. A., J.R.L., B.T.L. and P.L. designed the study and analyzed data. Y.Z., J.Y.X, J.L., T.T.M., R.R., D.K. and C.L. performed experiments and/or provided key scientific input. A.B. and E.dS. helped perform in vivo studies. Y.R.M.G., K.C.A., A.S., G.R. and B.T.L. helped identify clinical specimens and carried out chart review for emergent alterations. A.A. and J.R.L. helped carry out review of the clinical trial repository to identify emergent alterations. A.S., D.M., P.A. and J.R.L. performed data collection and analysis. A.D.C.P., J.S.R.-F. and B.W. helped carry out scDNA sequencing. K.S.A, B.R.L and M.B. helped carry out bulk sequencing studies and data analysis. Y.Z., Y.R.M.G., J.Y.X, A.A. and P.L. were the main writers of the manuscript. All other authors reviewed the manuscript and contributed to writing it. Author Contributions |
| ISSN: | 0028-0836 1476-4687 |
| DOI: | 10.1038/s41586-021-04065-2 |