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Cited by 68Lung Cancer Treatments and MutationsProtein Kinase Regulation and GTPase SignalingCancer Genomics and Diagnostics

Genomic landscape of clinically acquired resistance alterations in patients treated with KRASG12C inhibitors

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Riedl, J.M., Fece de la Cruz, F., Lin, J.J., Parseghian, C., Kim, J.E., Matsubara, H., Barnes, H., Caughey, B. +16 more·2025·Annals of Oncology
DOI 10.1016/j.annonc.2025.01.020PMC PMC12097956
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Abstract

Background Mutant-selective inhibitors of KRAS G12C (KRAS G12C i) have demonstrated efficacy in KRAS G12C cancers. However, resistance invariably develops, resulting in short-lived responses. We aimed to define the genomic landscape of acquired resistance to KRAS G12C i and to elucidate whether novel classes of KRAS inhibitors can overcome these resistance mechanisms. Methods To assess clinical frequencies of acquired resistance alterations, we evaluated genomic sequencing data from postprogression cell-free DNA samples in patients treated with KRAS G12C i at two United States cancer centers, alongside data from six previously published studies. Cell viability assays using engineered cell models were employed to functionally validate candidate resistance drivers and to evaluate novel classes of KRAS inhibitors. Results A total of 143 patients were analyzed. Most patients had non-small-cell lung cancer (NSCLC, n = 68) or colorectal cancer (CRC, n = 58) and were treated with single-agent KRAS G12C i ( n = 109) or combined with anti-EGFR antibodies ( n = 30). RAS/MAPK alterations emerged in 46% of patients ( n = 66), with 39% developing one or more new KRAS alterations ( n = 56) and 23% ( n = 33) showing multiple concurrent alterations. The genomic landscape of acquired alterations included KRAS -activating mutations (25% of patients), KRAS amplifications (22%), RAF/MAPK mutations/fusions (21%), KRAS switch-II pocket mutations (14%), and NRAS/HRAS mutations (8%). Notably, the proportion of patients with one or more acquired RAS/MAPK alteration was significantly higher in CRC compared with NSCLC (69% versus 26%, P < 0.001). Functional studies confirmed most alterations as resistance drivers. Sotorasib, adagrasib, and divarasib demonstrated distinct activity against KRAS switch-II pocket mutations, yet all were responsive to the RAS(ON) G12C-selective tri-complex inhibitor RM-018. The KRAS-selective inhibitor Pan KRAS-IN-1 effectively targeted KRAS -activating mutations, and the RAS(ON) multiselective tri-complex inhibitor RMC-7797 demonstrated high potency across all RAS alterations. Conclusions Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRAS G12C i detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations.

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  • About a third of relapsed tumors lack detectable genomic alterations, suggesting that non-genetic mechanisms also play a significant role in resistance to KRAS-EGFR dual therapy.

    “Moreover, about a third of relapsed tumors lack detectable genomic alterations,18,19 suggesting that non-genetic mechanisms also play a significant role in resistance to KRAS-EGFR dual therapy.”

    From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [19]

    The Discussion suggests that non-genetic mechanisms may contribute to resistance, particularly in NSCLC, but also cautions that sequencing may miss low-frequency alterations. The Results do not support the claimed one-third figure for KRAS–EGFR combination therapy: 90% of CRC patients receiving combination therapy had at least one acquired RAS/MAPK alteration. The paper therefore supports the possibility of non-genetic resistance, not the stated proportion or its attribution specifically to dual therapy. (LLM, conf=0.87)

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Research works printed but not linked: 2

  1. [8]Jänne PA, Riely GJ, Gadgeel SM Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation. New England Journal of Medicine 2022; 387 (2): 120– 131. 35658005
  2. [18]Awad MM, Liu S, Rybkin II Acquired Resistance to KRASG12C Inhibition in Cancer. New England Journal of Medicine 2021; 384 (25): 2382– 2393. 34161704 PMC8864540

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Authors
Riedl, J. M., Fece de la Cruz, F., Lin, J. J., Parseghian, C., Kim, J. E., Matsubara, H., Barnes, H., Caughey, B., Norden, B. L., Morales-Giron, A. A., Kushner, E. W., Ehnstrom, S., Nakamura, H., Patel, P. S., Ellis, H., Pappas, L., Vakaris, A., Gainor, J. F., Kopetz, S., Klempner, S. J., Parikh, A. R., Hata, A. N., Heist, R. S., & Corcoran, R. B.
Affiliations
  • Harvard University (US)
  • Medical University of Graz (AT)
  • Asan Medical Center (KR)
  • Massachusetts General Hospital (US)
Corresponding author
Corcoran, R.B.
ORCID
Venue
Annals of Oncology
Publisher
Elsevier BV
Published
2025-06
Volume
36
Issue
6
Pages
682-692
ISSN
0923-7534 (ISSN-L)
DOI
10.1016/j.annonc.2025.01.020
PMC
PMC12097956
OpenAlex
W4407131502
Cited by
68
References
42
Citations by year
2026: 48 · 2025: 20
FWCI
44.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Oncology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
Funders
  • Stand up to Cancer
  • National Institutes of Health National Cancer Institute (R01 CA262805)
  • Austrian Science Fund (J 4911-B)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
KRAS G12C inhibitors, acquired drug resistance, KRAS G12C, KRAS amplification, non-small cell lung cancer, colorectal cancer, sotorasib, adagrasib, divarasib, resistance mechanisms
MeSH terms
Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Genomics, Cell Line, Tumor

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