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Src-Dependent DBL Family Members Drive Resistance to Vemurafenib in Human Melanoma

Charlotte R Feddersen1, Jacob L Schillo1, Afshin Varzavand2

  • 1Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa.

Cancer Research
|August 17, 2019
PubMed

Insights

Drug resistance is common in melanoma patients treated with BRAF inhibitors. A genetic screen identified a DBL/RAC1/PAK signaling pathway driving this resistance, which can be blocked by saracatinib, offering new combination therapy options.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Selective BRAF inhibitors (BRAFi) show efficacy in advanced cutaneous melanoma with BRAF mutations.
  • Acquired drug resistance limits the long-term effectiveness of BRAFi therapy in most patients.

Purpose of the Study:

  • To identify novel gain-of-function mechanisms driving BRAFi resistance in melanoma.
  • To explore potential therapeutic strategies to overcome BRAFi resistance.

Main Methods:

  • Utilized a genetic screening approach in two independent melanoma cell lines to identify resistance drivers.
  • Conducted mechanistic studies to elucidate the function of identified resistance genes.
  • Tested the efficacy of a SRC inhibitor (saracatinib) in blocking resistance.

Main Results:

  • Identified known and novel drivers of BRAFi resistance, including DBL family members.
  • Discovered a DBL/RAC1/PAK signaling axis mediating resistance to current and next-generation BRAFis.
  • Demonstrated that saracatinib effectively inhibits DBL-driven BRAFi resistance.

Conclusions:

  • A straightforward genetic screening method can rapidly identify genes conferring resistance to MAPK inhibitors.
  • The DBL/RAC1/PAK pathway is a key mediator of acquired BRAFi resistance in melanoma.
  • Saracatinib represents a potential therapeutic agent for combination therapy to overcome BRAFi resistance.

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