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Concomitant BCORL1 and BRAF Mutations in Vemurafenib-Resistant Melanoma Cells

Luca Mologni1, Mariantonia Costanza1, Geeta Geeta Sharma1

  • 1Dept. of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Neoplasia (New York, N.Y.)
|April 2, 2018
PubMed

Insights

Drug resistance in melanoma can arise from BRAF mutations and BCORL1 alterations. A combination therapy with vemurafenib and sorafenib shows promise in overcoming this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRAFV600E mutations are common in melanoma, driving MAPK signaling and responding to targeted therapies like vemurafenib.
  • Drug resistance and disease recurrence are significant challenges in BRAF-mutant melanoma treatment due to MAPK pathway reactivation.
  • Mechanisms of resistance often involve complex genetic alterations affecting signaling pathways.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying vemurafenib resistance in BRAFV600E-mutant melanoma.
  • To identify co-occurring genetic alterations contributing to drug resistance.
  • To explore potential therapeutic strategies to overcome vemurafenib resistance.

Main Methods:

  • Analysis of vemurafenib-resistant A375 melanoma cells.
  • Characterization of genetic alterations including BRAF locus amplification and BCORL1 mutations.
  • Functional assays to assess the contribution of truncated p47BRAFV600E and mutant BCORL1Q1076H to resistance.
  • Transcriptomic analysis to understand molecular effects.
  • Drug sensitivity testing with vemurafenib and sorafenib.

Main Results:

  • Co-occurrence of an in-frame deletion in amplified BRAFV600E and a missense mutation in BCORL1 (BCORL1Q1076H) was identified in resistant cells.
  • Both truncated p47BRAFV600E and mutant BCORL1Q1076H were confirmed to contribute to vemurafenib resistance.
  • BCORL1 mutation exhibited complex loss- and gain-of-function effects, supported by transcriptomic data.
  • The pan-RAF inhibitor sorafenib effectively inhibited resistant cells and synergized with vemurafenib.

Conclusions:

  • Combined genetic alterations in BRAF and BCORL1 can drive vemurafenib resistance in melanoma.
  • The BCORL1Q1076H mutation presents complex functional consequences contributing to resistance.
  • Combination therapy with vemurafenib and sorafenib represents a promising strategy to overcome this specific type of BRAF-mutant melanoma resistance.

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