Mutational profiles associated with resistance in patients with BRAFV600E mutant colorectal cancer treated with cetuximab and encorafenib ± binimetinib or alpelisib
Open accessAbstract
Background: Treatment strategies inhibiting BRAF in combination with EGFR have been developed in patients with BRAF V600E mutant metastatic colorectal cancer, but intrinsic and secondary resistance remains a challenge. We aimed to investigate which genetic alterations cause intrinsic non-response and/or acquired resistance in these patients receiving therapies consisting of a backbone of BRAF and EGFR inhibition. Methods: This was a cohort study on genetic alterations in patients with BRAF V600E mutant advanced colorectal cancer treated with inhibitors of the MAPK pathway. We examined tumour tissue for genetic alterations at baseline, during treatment and at progression. Results: In total, 37 patients were included in this cohort. Genetic alterations in EGFR and in PIK3CA are associated with non-response. A greater fraction of non-responders (75%) versus responders (46%) had at least one genetic alteration in other genes than TP53 , APC or BRAF . Secondary resistance mutations ( n = 16 patients) were observed most frequently in the PI3K pathway ( n = 6) and in receptor tyrosine kinases ( n = 4), leading to increased upstream signalling. Conclusions: Genetic alterations in the PI3K and upstream receptor tyrosine kinases were mostly associated with intrinsic and acquired resistance. By understanding these alterations, simultaneous or alternating treatments with targeted inhibitors might improve response duration.
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Combined inhibition of BRAF and EGFR using encorafenib and cetuximab significantly improved disease outcome in patients with BRAFV600E mutant mCRC.
“Combined inhibition of BRAF and EGFR using encorafenib and cetuximab significantly improved disease outcome in patients with BRAFV600E mutant mCRC”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [37]
The Background (page unavailable) says encorafenib plus cetuximab produced improved response rates in BRAFV600E-mutant metastatic colorectal cancer and describes its outcome as the best reported among the regimens discussed. It does not establish a statistically significant improvement in disease outcome; the paper’s cohort results are descriptive rather than a comparative test of that claim. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIntrinsic and acquired resistance to encorafenib and cetuximab remains a major clinical challenge.
“but intrinsic and acquired resistance remains a major clinical challenge [37].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [37]
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ESMO consensus guidelines for the management of patients with metastatic colorectal cancer
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Sorted by citations
Xu, T., Wang, X., Wang, Z., Deng, T., Qi, C., Liu, D., Li, Y., Ji, C., Li, J., & Shen, L. (2022) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359221105022 · Cited by 38 · see citing works
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“Combined inhibition of BRAF and EGFR using encorafenib and cetuximab significantly improved disease outcome in patients with BRAF V600E mutant mCRC, but intrinsic and acquired resistance remains a major clinical challenge [37].”
- Authors
- Huijberts, S. C. F. A., Boelens, M. C., Bernards, R., & Opdam, F. L.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Huijberts, Sanne C. F. A.
- Opdam, Frans L.
- Venue
- British Journal of Cancer
- Published
- 2020-11-18
- Volume
- 124
- Issue
- 1
- Pages
- 176-182
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC7782586
- OpenAlex
- W3100313727
- Cited by
- 36
- References
- 3
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 1
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- British Journal of Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- cetuximab, encorafenib, binimetinib, alpelisib, MAPK pathway inhibitors, EGFR inhibition, acquired drug resistance, PIK3CA mutation, PI3K signaling, receptor tyrosine kinase, mutational landscape, tumor progression
- MeSH terms
- Cetuximab, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Carbamates, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Mutation, Retrospective Studies, Sulfonamides, Thiazoles, Biomarkers, Tumor, Colorectal Neoplasms, Cohort Studies, Drug Resistance, Neoplasm, Proto-Oncogene Proteins B-raf
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