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Growth suppression by dual BRAF(V600E) and NRAS(Q61) oncogene expression is mediated by SPRY4 in melanoma

Raj Kumar1, Ching-Ni Njauw1, Bobby Y Reddy1

  • 1Department of Dermatology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Oncogene
|January 18, 2019
PubMed

Insights

Melanoma research reveals that introducing a second cancer-driving gene (oncogene) can halt tumor growth, a phenomenon termed synthetic suppression. The gene SPRY4 mediates this effect, offering potential therapeutic targets for melanoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The interplay between oncogenic mutations in melanoma, specifically BRAF(V600E) and NRAS(Q61), is not fully understood.
  • An exclusionary relationship exists between these two mutations in melanoma, suggesting underlying regulatory mechanisms.

Purpose of the Study:

  • To investigate the mechanisms behind the mutual exclusivity of BRAF(V600E) and NRAS(Q61) mutations in melanoma.
  • To identify potential mediators of growth arrest when both oncogenes are simultaneously activated.

Main Methods:

  • Overexpression of NRAS(Q61) in BRAF(V600E) melanoma cell lines and vice versa.
  • Analysis of cell cycle arrest, senescence, and apoptosis.
  • Differential gene expression analysis to identify key mediators.
  • Functional studies involving SPRY4 ectopic expression and depletion.

Main Results:

  • Co-expression of BRAF(V600E) and NRAS(Q61) induced growth arrest, cell cycle arrest, senescence, and apoptosis in a subset of melanoma cells.
  • SPRY4 was identified as a key mediator of this 'synthetic suppression' response.
  • Ectopic SPRY4 expression mimicked the growth arrest, while SPRY4 depletion partially rescued the cells from oncogenic antagonism.

Conclusions:

  • SPRY4 acts as a mediator of synthetic suppression, contributing to the observed exclusivity between BRAF(V600E) and NRAS(Q61) mutations in melanoma.
  • Targeting the SPRY4 pathway presents a potential therapeutic strategy for NRAS(Q61) mutated melanomas.

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