Cited by 350Melanoma and MAPK PathwaysColorectal Cancer Treatments and StudiesLung Cancer Treatments and Mutations

BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation

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Corcoran, Ryan B., Dias-Santagata, Dora, Bergethon, Kristin, Iafrate, A. John, Settleman, Jeffrey, Engelman, Jeffrey A.·2010·Science Signaling

Abstract

Amplification of an upstream gene leads to resistance to cancer drugs targeted downstream.

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Crossref · 10.1126/scisignal.2001148

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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 measured
  • Pre-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].”

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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
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
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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