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

Cancer Cell. 2019 Jul 8;36(1):68-83.e9. doi: 10.1016/j.ccell.2019.05.015. Epub 2019 Jun 27.

Abstract

RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target.

Keywords: BRAF; EMT; MRTF; NF1; PTEN; RAC1; SRF; melanoma; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Expression
  • Humans
  • Male
  • Melanocytes / metabolism
  • Melanoma / etiology*
  • Melanoma / mortality
  • Melanoma / pathology*
  • Melanoma / therapy
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Mutation*
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / genetics
  • Serum Response Factor
  • Xenograft Model Antitumor Assays
  • rac1 GTP-Binding Protein / genetics*

Substances

  • Protein Kinase Inhibitors
  • RAC1 protein, human
  • Serum Response Factor
  • Proto-Oncogene Proteins B-raf
  • rac1 GTP-Binding Protein