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NRAS Q61K melanoma tumor formation is reduced by p38‐MAPK14 activation in zebrafish models and NRAS‐mutated human melanoma cells


Banik, Ishani; Cheng, Phil F; Dooley, Christopher M; Travnickova, Jana; Merteroglu, Munise; Dummer, Reinhard; Patton, Elizabeth E; Busch‐Nentwich, Elisabeth M; Levesque, Mitchell P (2021). NRAS Q61K melanoma tumor formation is reduced by p38‐MAPK14 activation in zebrafish models and NRAS‐mutated human melanoma cells. Pigment Cell & Melanoma Research, 34(2):150-162.

Abstract

Oncogenic BRAF and NRAS mutations drive human melanoma initiation. We used transgenic zebrafish to model NRAS‐mutant melanoma, and the rapid tumor onset allowed us to study candidate tumor suppressors. We identified P38α‐MAPK14 as a potential tumor suppressor in The Cancer Genome Atlas melanoma cohort of NRAS‐mutant melanomas, and overexpression significantly increased the time to tumor onset in transgenic zebrafish with NRAS‐driven melanoma. Pharmacological activation of P38α‐MAPK14 using anisomycin reduced in vitro viability of melanoma cultures, which we confirmed by stable overexpression of p38α. We observed that the viability of MEK inhibitor resistant melanoma cells could be reduced by combined treatment of anisomycin and MEK inhibition. Our study demonstrates that activating the p38α‐MAPK14 pathway in the presence of oncogenic NRAS abrogates melanoma in vitro and in vivo.
Significance

The significance of our study is in the accountability of NRAS mutations in melanoma. We demonstrate here that activation of p38α‐MAPK14 pathway can abrogate NRAS‐mutant melanoma which is contrary to the previously published role of p38α‐MAPK14 pathway in BRAF mutant melanoma. These results implicate that BRAF and NRAS‐mutant melanoma may not be identical biologically. We also demonstrate the translational benefit of our study by using a small molecule compound‐anisomycin (already in use for other diseases in clinical trials) to activate p38α‐MAPK14 pathway.

Abstract

Oncogenic BRAF and NRAS mutations drive human melanoma initiation. We used transgenic zebrafish to model NRAS‐mutant melanoma, and the rapid tumor onset allowed us to study candidate tumor suppressors. We identified P38α‐MAPK14 as a potential tumor suppressor in The Cancer Genome Atlas melanoma cohort of NRAS‐mutant melanomas, and overexpression significantly increased the time to tumor onset in transgenic zebrafish with NRAS‐driven melanoma. Pharmacological activation of P38α‐MAPK14 using anisomycin reduced in vitro viability of melanoma cultures, which we confirmed by stable overexpression of p38α. We observed that the viability of MEK inhibitor resistant melanoma cells could be reduced by combined treatment of anisomycin and MEK inhibition. Our study demonstrates that activating the p38α‐MAPK14 pathway in the presence of oncogenic NRAS abrogates melanoma in vitro and in vivo.
Significance

The significance of our study is in the accountability of NRAS mutations in melanoma. We demonstrate here that activation of p38α‐MAPK14 pathway can abrogate NRAS‐mutant melanoma which is contrary to the previously published role of p38α‐MAPK14 pathway in BRAF mutant melanoma. These results implicate that BRAF and NRAS‐mutant melanoma may not be identical biologically. We also demonstrate the translational benefit of our study by using a small molecule compound‐anisomycin (already in use for other diseases in clinical trials) to activate p38α‐MAPK14 pathway.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Oncology
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Health Sciences > Dermatology
Uncontrolled Keywords:General Biochemistry, Genetics and Molecular Biology, Oncology, Dermatology
Language:English
Date:1 March 2021
Deposited On:09 Mar 2021 16:26
Last Modified:24 Jun 2024 01:48
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1755-1471
OA Status:Closed
Publisher DOI:https://doi.org/10.1111/pcmr.12925
PubMed ID:32910840