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Updated: May 2, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

Luping Lin1, Saurabh Asthana, Elton Chan

  • 1Departments of Medicine and Epidemiology and Biostatistics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.

Proceedings of the National Academy of Sciences of the United States of America
|February 20, 2014
PubMed

Insights

Non-small cell lung cancers (NSCLCs) with BRAF(V600E) mutations initially respond to BRAF inhibitors but rapidly develop resistance. This resistance occurs via loss of BRAF(V600E) or through EGFR signaling, impacting AKT activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • BRAF kinase mutations are present in 6-8% of non-small cell lung cancers (NSCLCs).
  • The clinical significance and underlying mechanisms of BRAF mutations in NSCLC remain unclear.
  • BRAF(V600E) mutations represent a targetable driver in a subset of NSCLCs.

Purpose of the Study:

  • To investigate the mechanisms of BRAF inhibitor resistance in BRAF(V600E)-mutated NSCLC.
  • To identify biomarkers associated with resistance to BRAF inhibition.
  • To elucidate the crosstalk between BRAF and EGFR signaling pathways in NSCLC.

Main Methods:

  • Utilized human NSCLC cell lines harboring BRAF(V600E) mutations.
  • Analyzed molecular alterations leading to BRAF inhibitor resistance.
  • Investigated autocrine signaling pathways, including EGFR and c-Jun.
  • Validated biomarkers in clinical NSCLC specimens resistant to BRAF inhibitors.

Main Results:

  • NSCLC cells with BRAF(V600E) mutations show initial sensitivity to BRAF inhibitors.
  • Two primary resistance mechanisms were identified: loss of full-length BRAF(V600E) or constitutive autocrine EGFR signaling.
  • EGFR-driven resistance is associated with c-Jun-mediated ligand expression and hyperphosphorylated AKT.
  • Hyperphosphorylated AKT was validated as a biomarker in resistant NSCLC clinical samples.

Conclusions:

  • BRAF(V600E)-mutated NSCLCs develop resistance through distinct molecular pathways.
  • EGFR signaling, driven by c-Jun, is a key mechanism of acquired resistance.
  • Hyperphosphorylated AKT serves as a potential biomarker for EGFR-driven resistance.
  • Understanding these mechanisms can inform strategies to overcome BRAF inhibitor resistance in NSCLC.
Keywords:
combination therapytargeted therapy

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