BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation
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Amplification of an upstream gene leads to resistance to cancer drugs targeted downstream.
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The association of BRAF or ARID1A co-alterations with shorter progression-free survival is mechanistically plausible and consistent with studies implicating these genes in EGFR inhibitor resistance.
“Our observation that BRAF or ARID1A co-alterations are associated with shorter progression-free survival is mechanistically plausible and consistent with studies implicating these genes in EGFR inhibitor resistance. 23-27”
From Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial (2024) · cites this paper as [24]
The Introduction and Discussion show that BRAF amplification can cause resistance to MEK and BRAF inhibitors, providing a mechanistic rationale for resistance to targeted therapy. They do not implicate BRAF or ARID1A in EGFR inhibitor resistance; the Discussion’s EGFR-inhibitor examples concern other genes. The shorter progression-free survival association is presented as the citing authors’ own observation, not a finding attributed to this paper. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPre-clinical studies and early trials have demonstrated improved responses to combined MEK and BRAF inhibition.
“Pre-clinical studies and early trials have demonstrated improved responses to combined MEK and BRAF inhibition [37,38].”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [37]
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- Authors
- Corcoran, R. B., Dias-Santagata, D., Bergethon, K., Iafrate, A. J., Settleman, J., & Engelman, J. A.
- Affiliations
- Harvard University (US)
- Corresponding author
- Settleman, Jeffrey
- Engelman, Jeffrey A.
- Venue
- Science Signaling
- Published
- 2010-11-23
- Volume
- 3
- Issue
- 149
- Pages
- ra84-ra84
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC3372405
- OpenAlex
- W1990376228
- Cited by
- 350
- References
- 29
- Citations by year
- 2026: 4 · 2025: 16 · 2024: 12 · 2023: 14 · 2022: 19 · 2021: 24 · 2020: 20 · 2019: 27 · 2018: 24 · 2017: 23 · 2016: 19 · 2015: 28 · 2014: 25 · 2013: 33 · 2012: 41
- FWCI
- 12.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA127003, R01CA140594, P50CA090578, R01CA135257, K08CA120060, R01CA140597, T32CA071345, R01CA137008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- MEK inhibitors, acquired drug resistance, BRAF V600E mutation, selumetinib, MEK inhibitor resistance, BRAF inhibitor resistance, colorectal cancer, melanoma, ERK1/2 phosphorylation, MEK phosphorylation, MAPK signaling, combination therapy
- MeSH terms
- Analysis of Variance, Benzimidazoles, Gene Amplification, Humans, Phosphorylation, Blotting, Western, Signal Transduction, In Situ Hybridization, Fluorescence, Sequence Analysis, DNA, DNA Primers, Drug Resistance, Neoplasm, Mutation, Missense, Inhibitory Concentration 50, Mitogen-Activated Protein Kinase Kinases, RNA, Small Interfering, Cell Line, Tumor, Proto-Oncogene Proteins B-raf
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