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 found in patients treated with sotorasib or adagrasib monotherapy.
“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]
The Results section reports acquired NRAS and BRAF mutations, RTK activation, and MYC amplification in colorectal cancer patients treated with adagrasib plus cetuximab or sotorasib plus panitumumab—not monotherapy. The Introduction discusses resistance to KRAS G12C monotherapy, but does not report this full list for monotherapy patients. RTK activation and MYC amplification also cannot all be described as mutations. (LLM, conf=0.90)
Experimental — accuracy not yet measuredKRAS G12C amplification was a consistent resistance mechanism that increased in frequency over the duration of treatment of CRC patients and cell lines treated with combinations of KRAS and EGFR inhibitors.
“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]
The Results section on resistance dynamics in ctDNA reports that KRAS G12C amplification increased steadily with tumor-marker response during treatment in CRC patients. The Results section on resistance mechanisms also identifies amplification in a resistant cell line, supporting its recurrence, but does not show that its frequency increased over the treatment period in cell lines. Page numbers are unavailable in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPost-treatment analysis of NSCLC and CRC samples from patients treated with sotorasib or adagrasib identified de novo oncogenic mutations secondary to treatment, including multiple amplifications and point mutations in KRAS G12C itself.
“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]
The Results section reports resistance-associated KRAS G12C amplification and KRAS point mutations in samples from CRC patients treated with adagrasib plus cetuximab or sotorasib plus panitumumab. It does not report post-treatment analysis of NSCLC samples, and it describes the alterations as emergent at resistance rather than establishing that treatment caused de novo mutations. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCells that become resistant to the combination of KRASi and EGFRi are sensitive to mTOR inhibition.
“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]
The Results section, “Exploiting the new steady state after drug withdrawal to overcome resistance” (page not provided), reports that resistant RW7213 cells were more sensitive to the mTOR inhibitor AZD8055 after withdrawal of the KRAS G12C–EGFR inhibitor combination than during continuous exposure. The claim omits those conditions and generalizes the finding to resistant cells broadly; the paper frames mTOR blockade as a potential approach for resistant cancers with KRAS G12C amplification following drug withdrawal. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEmerging genetic alterations have been shown to mediate resistance to KRAS G12C inhibitors combined with EGFR inhibitors in CRC patients.
“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]
The Results section ('Mechanisms of resistance to combined KRAS G12C and EGFR inhibition'; no page available) reports emergent genetic alterations in CRC patients who progressed on combination treatment. The 'Resistance dynamics' Results section identifies KRAS G12C amplification as a substantial resistance mechanism, but describes many other patient alterations as low-frequency and putative; the claim overstates how firmly those alterations were shown to mediate resistance. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Secondary RAS mutations and other genetic alterations are one of the most common mechanisms of acquired resistance to KRAS inhibitors in patients.
“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]
The Results section on patient ctDNA identifies acquired genetic alterations, including KRAS G13D and NRAS Q61K mutations, during KRAS G12C–EGFR inhibition in colorectal cancer. It does not establish secondary RAS mutations as one of the most common resistance mechanisms in patients: those mutations were low-frequency and sometimes disappeared, whereas KRAS G12C amplification tracked clinical progression and was described as driving more of the resistance phenotype. The claim also generalizes beyond the combination treatment studied here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAnalysis of 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.
“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]
The Results section (‘Mechanisms of resistance to combined KRAS G12C and EGFR inhibition’; page unavailable) reports cfDNA analysis of 12 CRC patients receiving the stated combinations and identifies acquired KRAS and NRAS mutations and KRAS G12C amplification. The passages in our copy do not establish that these alterations occurred in 7 of 12 patients (58.3%), so the specific percentage is unsupported. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn 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.
“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]
Co-inhibiting KRAS and EGFR can shut down feedback loops activated by KRAS monotherapy.
“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]
Recent studies have identified mechanisms of resistance to KRAS-EGFR combination including secondary KRAS mutations, alterations in genes upstream or downstream of KRAS, and alterations in other RAS homologs.
“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]
Multiple resistance mutations often emerge in relapsed tumors within the same patient.
“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]
Upon disease progression with divarasib plus cetuximab, 92.9% of profiled patients had at least one genomic alteration that may be associated with treatment resistance, higher than 30.2% for patients treated with divarasib or other KRAS G12C inhibitors as single agent.
“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]
PIK3CA mutations can confer acquired resistance to KRAS G12C inhibitor and KRAS G12C inhibitor-cetuximab combination therapy in patients with NSCLC and CRC.
“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]
The Results section identifies acquired alterations in CRC after KRAS G12C inhibitor–EGFR antibody treatment, but the passages found do not identify PIK3CA mutations as a resistance mechanism. Searches for “PIK3CA mutations acquired resistance” and “PIK3CA” found no passage addressing that mutation; the cited paper’s copy therefore does not verify the specific claim about PIK3CA in NSCLC or CRC. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe observed spectrum of acquired genomic alterations 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.
“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 <i>KRAS</i> G12C-Mutated Metastatic Colorectal Cancer (2024) · cites this paper as [31]
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Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated <i>KRAS</i> G12C
Fakih, M. G., Salvatore, L., Esaki, T., Modest, D. P., Lopez-Bravo, D. P., Taieb, J., Karamouzis, M. V., Ruiz-Garcia, E., Kim, T.-W., Kuboki, Y., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2308795 · Cited by 398 · see citing works
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Self-citationKRAS inhibitors: resistance drivers and combinatorial strategies
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Self-citationDivarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial
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“%) of patients profiled had at least one genomic alteration that may be associated with treatment resistance similarly to two previous reports 26,27 , which is higher than that of patients treated with divarasib (30.2”
ResultInfluentialModulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors
Lv, X., Lu, X., Cao, J., Luo, Q., Ding, Y., Peng, F., Pataer, A., Lu, D., Han, D., Malmberg, E., et al. (2023) · Science · doi:10.1126/science.abn4180 · Cited by 123 · see citing works
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A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer
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Response and Resistance to RAS Inhibition in Cancer
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KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
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“The findings emphasize the TME’s role in resistance and suggest therapeutic strategies like combining TGF β or CCL2/CCL7-CCR2 targeting with KRAS inhibitors [54].”
BackgroundMethodInfluentialKRAS: the Achilles’ heel of pancreas cancer biology
Drizyte‐Miller, K., Talabi, T., Somasundaram, A., Cox, A. D., & Der, C. J. (2025) · Journal of Clinical Investigation · doi:10.1172/jci191939 · Cited by 63 · see citing works
Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas
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Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver
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Neutrophil extracellular traps in tumor progression and immunotherapy
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Biological insights in non-small cell lung cancer
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KRAS G12C-mutant driven non-small cell lung cancer (NSCLC)
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The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC
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Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment
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Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer
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“7,17,18 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.”
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- 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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