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Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer
Open accessPublished version of a preprint
Abstract
With the combination of KRASG12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRASG12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRASG12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance. Significance: Clinical resistance to KRASG12C–EGFR inhibition primarily prevents suppression of ERK signaling. Most resistance mechanisms are subclonal, whereas KRASG12C amplification rises over time to drive a higher portion of resistance. This recurrent resistance mechanism leads to oncogene-induced senescence upon drug withdrawal and creates a potential vulnerability to senolytic approaches. Watch the interview with Sandra Misale, PhD, recipient of the 2025 Cancer Discovery Early Career Award: https://vimeo.com/1100471486 This article is highlighted in the In This Issue feature, p. 1
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“Acquired mutations of NRAS, BRAF, RTK, and MYC were also found in patients treated with sotorasib or adagrasib monotherapy [49, 51, 53, 54].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [53]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“KRAS G12C amplification was a consistent resistance mechanism that increased in frequency over the duration of the treatment of CRC patients and cell lines treated with combinations of KRAS and EGFR inhibitors [101].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [101]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Post-treatment analysis of NSCLC and CRC samples from patients treated with either sotorasib or adagrasib identified de novo oncogenic mutations secondary to treatment, including multiple amplifications and point mutations in KRAS G12C itself [101].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [101]
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“Of note, cells that become resistant to the combination of KRASi and EGFRi are sensitive to mTOR inhibition [101].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [101]
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“Furthermore, emerging genetic alterations have been shown to mediate resistance to KRAS G12C inhibitors combined with EGFR inhibitors in CRC patients.”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [53]
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“Genetic alterations, especially secondary RAS mutations, have been identified as one of the most common mechanisms of acquired resistance to KRAS inhibitors in patients [49, 51–55].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [53]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Analysis of cell-free DNA (cfDNA) in 12 CRC patients treated with sotorasib/panitumumab or adagrasib/cetuximab combinations identified secondary RAS mutations, KRAS amplifications, or both in 58.3% of sampled patients [53].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [53]
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“In CRC patients co-treated with KRASi and EGFRi, low-frequency non-G12C KRAS mutations were detected in circulating tumor DNA, but were not well maintained over time [101].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [101]
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“Co-inhibiting KRAS and EGFR can shut down feedback loops activated by KRAS monotherapy [96,101,124].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [101]
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In the citing paper
“Recent studies have identified several mechanisms of resistance to this combination, including secondary KRAS mutations, alterations in genes upstream or downstream of KRAS, and alterations in other RAS homologs.7,17,18”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [17]
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“Notably, multiple resistance mutations often emerge in relapsed tumors within the same patient,7,17,18 which poses challenges to targeting heterogenous resistance mechanisms at the time of progressing disease.”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [17]
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“Upon disease progression with divarasib plus cetuximab, the majority (92.9%) of patients profiled had at least one genomic alteration that may be associated with treatment resistance similarly to two previous reports26,27, which is higher than that of patients treated with divarasib (30.2%) or other KRAS G12C inhibitors as single agent11,28,29.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [26]
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“Previous reports have shown that PIK3CA mutations can confer acquired resistance to KRAS G12C inhibitor and KRAS G12C inhibitor–cetuximab combination therapy in patients with NSCLC and CRC34–36.”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [35]
Experimental — accuracy not yet measuredIn the citing paper
“This is in line with previous reports of acquired KRAS mutations and acquired RTK/RAS/MAPK/PI3K pathway alterations following concurrent KRASG12C and EGFR inhibition in colorectal cancer (31, 32).”
From Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRAS G12C-Mutated Metastatic Colorectal Cancer (2024) · cites this paper as [31]
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Metadata
- Authors
- Yaeger, R., Mezzadra, R., Sinopoli, J., Bian, Y., Marasco, M., Kaplun, E., Gao, Y., Zhao, H., Paula, A. D. C., Zhu, Y., Perez, A. C., Chadalavada, K., Tse, E., Chowdhry, S., Bowker, S., Chang, Q., Qeriqi, B., Weigelt, B., Nanjangud, G. J., Berger, M. F., Der-Torossian, H., Anderes, K., Socci, N. D., Shia, J., Riely, G. J., Murciano-Goroff, Y. R., Li, B. T., Christensen, J. G., Reis-Filho, J. S., Solit, D. B., de Stanchina, E., Lowe, S. W., Rosen, N., & Misale, S.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Boundless Bio (United States) (US)
- 9Mirati Therapeutics, Inc., San Diego, California.
- Mirati Therapeutics (United States) (US)
- 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
- 4Antitumour Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
- Corresponding author
- Yaeger, Rona
- Misale, Sandra
- ORCID
- Yaeger, Rona
- Mezzadra, Riccardo
- Sinopoli, Jenna
- Bian, Yu
- Marasco, Michelangelo
- Kaplun, Esther
- Gao, Yijun
- Zhao, HuiYong
- Paula, Arnaud Da Cruz
- Zhu, Yingjie
- Perez, Almudena Chaves
- Chadalavada, Kalyani
- Tse, Edison
- Chowdhry, Sudhir
- Bowker, Sydney
- Chang, Qing
- Qeriqi, Besnik
- Weigelt, Britta
- Nanjangud, Gouri J.
- Berger, Michael F.
- Der-Torossian, Hirak
- Anderes, Kenna
- Socci, Nicholas D.
- Shia, Jinru
- Riely, Gregory J.
- Murciano-Goroff, Yonina R.
- Li, Bob T.
- Christensen, James G.
- Reis-Filho, Jorge S.
- Solit, David B.
- de Stanchina, Elisa
- Lowe, Scott W.
- Rosen, Neal
- Misale, Sandra
- Venue
- Cancer Discovery
- Published
- 2022-11-10
- Volume
- 13
- Issue
- 1
- Pages
- 41-55
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC9827113
- OpenAlex
- W4308683759
- Cited by
- 144
- References
- 51
- Citations by year
- 2026: 37 · 2025: 49 · 2024: 36 · 2023: 22
- FWCI
- 11.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Discovery (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institutes of Health (R01 CA233736, U54 OD020355, P30 CA008748, K30 UL1TR00457)
- Cancer Research Institute (CRI 3441)
- Conquer Cancer Foundation (YIA)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS G12C, EGFR inhibition, acquired drug resistance, colorectal cancer, KRAS amplification, ERK signaling, oncogene-induced senescence, mTOR signaling, circulating tumor DNA, senolytic therapy, patient-derived xenografts
- MeSH terms
- Animals, Disease Models, Animal, Humans, Mutation, Colorectal Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, ErbB Receptors
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