The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers
Open accessAbstract
Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy. The mechanisms underlying this acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs. The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.
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Studies of pre-treatment and post-treatment samples identify multiple mechanisms of tumor evolution via low-frequency pre-existing mutations that expand after treatment and/or previously undetectable mutations induced by therapy de novo.
“Studies of pre-treatment and post-treatment samples identify multiple mechanisms of tumor evolution both via low-frequency pre-existing mutations that expand after treatment and/or previously undetectable mutations that are induced by therapy de novo [99,100].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [100]
The study’s analysis of longitudinal samples supports expansion of low-frequency resistance mutations already present before panitumumab therapy. It does not support the claim that therapy induced mutations de novo: the paper reports that, for each analyzed lesion, it rejected the possibility that the observed KRAS mutations were absent at treatment start (>95% confidence). The supplied copy labels this passage “Abstract” and gives no page number. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPatients with advanced WT RAS colorectal cancer commonly and often rapidly acquire resistance to anti-EGFR monotherapy.
“and patients commonly, and often rapidly, acquire resistance [5].”
From Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer (2020) · cites this paper as [5]
The Abstract says WT KRAS colorectal tumors almost always develop resistance within several months of EGFR blockade. It also reports clinically evident progression at 23 ± 10 weeks in 24 patients with WT KRAS tumors receiving panitumumab monotherapy. These passages support common, relatively rapid resistance, but establish it for WT KRAS tumors rather than specifically for the broader RAS-wild-type classification in the claim. (LLM, conf=0.84)
Experimental — accuracy not yet measuredKRAS acquired mutations are responsible for secondary resistance to anti-EGFR therapies in CRC.
“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 [23]
KRAS point mutations and gene copy number gains are responsible for acquired resistance in 38-60% of patients who relapse on cetuximab or panitumumab.
“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 [37]
KRAS alterations can be identified noninvasively 5-10 months before radiographic disease progression by analyzing cell-free circulating tumor DNA.
“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 [37]
BRAF (V600E) and MAP2K1/MEK1 (K57T, K57N, I99_K104 deletion, and E102_I103 deletion) can cause acquired drug resistance.
“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 [111]
ctDNA can be readily detected in advanced NSCLC patients, and sensitive genotyping assays can detect mutations in ctDNA.
“ctDNA can be readily detected in advanced NSCLC patients, and several studies have shown that highly sensitive genotyping assays can detect mutations in ctDNA (20–26).”
In KRAS wild-type colorectal cancers that developed resistance to cetuximab, emergence of KRAS mutations was observed as a resistance mechanism by repeat biopsies and circulating tumor DNA.
“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 Diaz et al., 2012
Non-invasive measures such as molecular interrogation of circulating tumor cells or plasma DNA may help capture the heterogeneity of resistance in patients.
“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 Diaz et al., 2012
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- Authors
- Diaz Jr, L. A., Williams, R. T., Wu, J., Kinde, I., Hecht, J. R., Berlin, J., Allen, B., Bozic, I., Reiter, J. G., Nowak, M. A., Kinzler, K. W., Oliner, K. S., & Vogelstein, B.
- Affiliations
- Amgen (United States) (US)
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- Vanderbilt University Medical Center (US)
- Harvard University (US)
- Corresponding author
- Oliner, Kelly S.
- ORCID
- Venue
- Nature
- Published
- 2012-06
- Volume
- 486
- Issue
- 7404
- Pages
- 537-540
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3436069
- OpenAlex
- W2116731538
- Cited by
- 1,713
- References
- 32
- Citations by year
- 2026: 33 · 2025: 45 · 2024: 62 · 2023: 73 · 2022: 106 · 2021: 100 · 2020: 109 · 2019: 155 · 2018: 141 · 2017: 167 · 2016: 187 · 2015: 186 · 2014: 169 · 2013: 141 · 2012: 37
- FWCI
- 83.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Institute of Science and Technology Austria (submittedVersion, other-oa)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (n01cn43309-10-0-1)
- National Cancer Institute (N01 CN043309, CA095103, CA 57345, R01CA129825, CA43460, N01 CN43309, P50CA095103, R37CA043460, R01CA057345, CA129825, P50CA062924, R37CA057345, CA 62924)
- National Institute of General Medical Sciences (R01GM058008, R01GM078986)
- 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
- acquired drug resistance, KRAS mutation, EGFR inhibition, anti-EGFR monoclonal antibody, panitumumab, cetuximab, colorectal cancer, circulating tumor DNA, clonal evolution, combination therapy, tumor recurrence
- MeSH terms
- Panitumumab, Antibodies, Monoclonal, DNA, Neoplasm, Humans, Mutation, Proto-Oncogene Proteins, Genes, ras, Selection, Genetic, Time Factors, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), ras Proteins, Drug Resistance, Neoplasm, Evolution, Molecular, ErbB Receptors
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