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Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer
Open accessAbstract
A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.
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In the citing paper
“Patients who initially respond to anti-EGFR develop acquired resistance within 12 to 18 months due to secondary mutations in KRAS genes, EGFR exodomain alteration, and clonal selection [9].”
From Overcoming Resistance to Anti-EGFR Therapies: Mechanisms of Cetuximab and Panitumumab Resistance and Emerging Combination Strategies (2026) · cites this paper as [9]
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In the citing paper
“We and others previously reported that KRAS acquired mutations are responsible for secondary resistance to anti-EGFR therapies in CRC(22, 23).”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [22]
The cited source says what the claim attributes to it.
In the citing paper
“Patients who fail to respond to therapy initially exhibit intrinsic resistance, whereas those who relapse after initial response are associated with acquired resistance [9].”
From Overcoming Resistance to Anti-EGFR Therapies: Mechanisms of Cetuximab and Panitumumab Resistance and Emerging Combination Strategies (2026) · cites this paper as [9]
In the citing paper
“Emergence of KRAS amplification and acquisition of secondary KRAS mutations (G12C, G12D, G13D and Q61H) was detected as one mechanism of acquired resistance in metastatic CRC patients, who relapsed on cetuximab or panitumumab treatment (78, 79).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [78]
In the citing paper
“KRAS point mutations and gene copy number gains are responsible not only for primary but also for acquired resistance in 38–60 % of patients who relapse on cetuximab or panitumumab [37-39].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [38]
In the citing paper
“KRAS alterations could be identified noninvasively 5–10 months before radiographic disease progression by analyzing cell-free circulating tumor DNA (ctDNA) [37, 38].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [38]
In the citing paper
“however, the proof of principle that such an approach could complement tumor biopsy and provide an early warning of acquired resistance has been established [38, 41, 136].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [38]
In the citing paper
“To address these challenges, Mirati Therapeutics conducted high-resolution crystal structure analyses of compounds bound to mutant KRAS proteins, optimizing these compounds to develop MRTX1133, a non-covalent, selective inhibitor for KRAS G12D [60].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [60]
In the citing paper
“For instance, BRAF (V600E) and MAP2K1/MEK1 (K57T, K57N, I99_K104 deletion, and E102_I103 deletion) can also cause acquired drug resistance [94, 108–111].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [110]
In the citing paper
“By performing repeat biopsies and evaluating circulating tumor DNA, investigators observed the emergence of KRAS mutations as a resistance mechanism (Diaz et al., 2012; Misale et al., 2012).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Misale et al., 2012
In the citing paper
“non-invasive measures such as molecular interrogation of circulating tumor cells or plasma DNA may help capture the heterogeneity of resistance in patients, as was done to identify the development of KRAS mutations in colorectal cancers that acquire resistance to cetuximab (Diaz et al., 2012; Misale et al., 2012).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Misale et al., 2012
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Metadata
- Authors
- Misale, S., Yaeger, R., Hobor, S., Scala, E., Janakiraman, M., Liska, D., Valtorta, E., Schiavo, R., Buscarino, M., Siravegna, G., Bencardino, K., Cercek, A., Chen, C.-T., Veronese, S., Zanon, C., Sartore-Bianchi, A., Gambacorta, M., Gallicchio, M., Vakiani, E., Boscaro, V., Medico, E., Weiser, M., Siena, S., Di Nicolantonio, F., Solit, D., & Bardelli, A.
- Affiliations
- Candiolo Cancer Institute (IT)
- Memorial Sloan Kettering Cancer Center (US)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- University of Turin (IT)
- IFOM (IT)
- Corresponding author
- Solit, David
- Bardelli, Alberto
- ORCID
- Venue
- Nature
- Published
- 2012-06
- Volume
- 486
- Issue
- 7404
- Pages
- 532-536
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3927413
- OpenAlex
- W2062109911
- Cited by
- 1,889
- References
- 25
- Citations by year
- 2026: 75 · 2025: 73 · 2024: 81 · 2023: 115 · 2022: 129 · 2021: 138 · 2020: 134 · 2019: 163 · 2018: 161 · 2017: 171 · 2016: 177 · 2015: 163 · 2014: 145 · 2013: 133 · 2012: 28
- FWCI
- 73.66
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Memorial Sloan-Kettering Cancer Center
- European Commission (259015)
- Associazione Italiana per la Ricerca sul Cancro (5 x mille)
- Regione Piemonte
- National Cancer Institute (R01CA127240, P30CA008748, T32CA009207, R25CA020449)
- 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 mutation, acquired drug resistance, anti-EGFR therapy, cetuximab resistance, colorectal cancer, EGFR, K-ras oncogene, circulating tumor DNA, tumor subclones, MEK inhibition, combination therapy, metastatic colorectal cancer, tumor heterogeneity
- MeSH terms
- Cetuximab, Panitumumab, Alleles, Antibodies, Monoclonal, Humans, Mutation, Promoter Regions, Genetic, Proto-Oncogene Proteins, Genes, ras, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Disease Progression, ras Proteins, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinase Kinases, Cell Line, Tumor, Antibodies, Monoclonal, Humanized, ErbB Receptors
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