Growth Suppression by Dual BRAF(V600E) and NRAS(Q61) Oncogene Expression is Mediated by SPRY4 in Melanoma

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2019 Jan 18

PMID 30651601

Citations 9

Authors

Raj Kumar

Ching-Ni Njauw

Bobby Y Reddy

Zhenyu Ji

Anpuchchelvi Rajadurai

Nikolai Klebanov

Hensin Tsao

Affiliations

Soon will be listed here.

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.

Citing Articles

Signaling Switching from Hedgehog-GLI to MAPK Signaling Potentially Serves as a Compensatory Mechanism in Melanoma Cell Lines Resistant to GANT-61.

Pitesa N, Kurtovic M, Bartonicek N, Gkotsi D, conkas J, Petric T Biomedicines. 2023; 11(5).

PMID: 37239024 PMC: 10216463. DOI: 10.3390/biomedicines11051353.

SPRY4 inhibits and sensitizes the primary KIT mutants in gastrointestinal stromal tumors (GISTs) to imatinib.

Li S, Zhao S, Liang N, Zhang S, Zhang L, Zhou L Gastric Cancer. 2023; 26(5):677-690.

PMID: 37222910 DOI: 10.1007/s10120-023-01402-4.

The journey from melanocytes to melanoma.

Centeno P, Pavet V, Marais R Nat Rev Cancer. 2023; 23(6):372-390.

PMID: 37095242 DOI: 10.1038/s41568-023-00565-7.

Li M, Long X, Bu W, Zhang G, Deng G, Liu Y Front Immunol. 2023; 14:1112181.

PMID: 36875110 PMC: 9975150. DOI: 10.3389/fimmu.2023.1112181.

Mefloquine induces ER stress and apoptosis in BRAFi-resistant A375-BRAF /NRAS malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model.

Jandova J, Park S, Corenblum M, Madhavan L, Snell J, Rounds L Mol Carcinog. 2022; 61(6):603-614.

PMID: 35417045 PMC: 9133119. DOI: 10.1002/mc.23407.

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