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

Abstract

The underlying forces that shape mutational patterns within any type of cancer have been poorly characterized. One of the best preserved exclusionary relationships is that between BRAF(V600E) and NRAS(Q61) in melanomas. To explore possible mechanisms which could explain this phenomenon, we overexpressed NRAS(Q61) in a set of BRAF(V600E) melanoma lines and vice versa. Controlled expression of a second activating oncogene led to growth arrest (“synthetic suppression”) in a subset of cells, which was accompanied by cell cycle arrest and senescence in several melanoma cell lines along with apoptosis. Through differential gene expression analysis, we identified SPRY4 as the potential mediator of this synthetic response to dual oncogene suppression. Ectopic introduction of SPRY4 recapitulated the growth arrest phenotype of dual BRAF(V600E)/NRAS(Q61) expression while SPRY4 depletion led to a partial rescue from oncogenic antagonism. This study thus defined SPRY4 as a potential mediator of synthetic suppression, which is likely to contribute to the observed exclusivity between BRAF(V600E) and NRAS(Q61R) mutations in melanoma. Further leverage of the SPRY4 pathway may also hold therapeutic promise for NRAS(Q61) melanomas.

Oncogenetic network estimation with disjunctive Bayesian networks

“…BRAF exhibits mutual exclusivity relationship with NRAS and NF1. More specifically, hotspot mutations in the V600 codon of BRAF and Q61 codon of NRAS have been observed to be mutually exclusive even in single-cell level [41] and are suggested to be synthetically lethal [42,43]. On the other hand, nonhotspot mutations of each of the three subtype-determining genes can co-occur with hotspot mutations of other ones [38].…”

Circulating miRNAs in Small Extracellular Vesicles Secreted by a Human Melanoma Xenograft in Mouse Brains

“…In addition, NRAS mutations cause the constitutive activation of the MEK/MAPK signaling pathway. The double gene alteration could lead to the over-activation of the RAS/RAF/mitogen activated protein kinase-signaling pathway, promoting senescence [78,79]. Our idea is that sEVs released by tumor cells with the BRAF mutation harbor messages to avoid such "oncogene antagonism" by targeting NRAS in the recipient cells, which potentially harbor NRAS mutations.…”

Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities

“…Aging-associated changes [ 127,128] Ionizing irradiation X-ray, -radiation, UV light Cancer regression accompanied by side effects [ 125,126] Oncogene activation HRas, KRas, NRas, BRAF Cancer progression or suppression [129][130][131] Loss of tumor suppressors p53, PTEN Tumor inhibition; cancer progression [ 132,133] Oxidative stress Inducers of reactive oxygen species (e.g., paraquat, hydrogen peroxide)…”