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RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and

Daniël A Lionarons1, David C Hancock1, Sareena Rana2

  • 1Oncogene Biology, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.

Cancer Cell
|July 2, 2019
PubMed

Insights

The RAC1 P29S mutation promotes melanoma development and therapy resistance by activating specific pathways. Inhibiting the SRF/MRTF pathway can reverse resistance, offering a potential therapeutic strategy for melanoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • RAC1 P29 is a frequent mutation in cutaneous melanoma.
  • Understanding RAC1's role is crucial for melanoma treatment.

Purpose of the Study:

  • Investigate the function of RAC1 P29S in melanoma.
  • Identify therapeutic targets for RAC1-driven melanoma.

Main Methods:

  • Studied RAC1 P29S in mouse models.
  • Analyzed gene expression and protein activation.
  • Assessed drug resistance mechanisms.

Main Results:

  • RAC1 P29S activates PAK, AKT, and SRF/MRTF pathways.
  • This leads to a melanocytic to mesenchymal transition.
  • RAC1 P29S drives melanoma initiation and BRAF inhibitor resistance.
  • Resistance is reversed by SRF/MRTF inhibitors.

Conclusions:

  • RAC1 P29S is a key driver of melanoma initiation.
  • It mediates resistance to BRAF inhibitors.
  • SRF/MRTF pathway is a potential therapeutic target in melanoma.
Keywords:
BRAFEMTMRTFNF1PTENRAC1SRFmelanomap53

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