Taming the Wild-Types: Targeting PAK1 in Melanomas That Lack BRAF Mutations

Menée in vitro et in vivo, cette étude suggère l'intérêt d'un traitement par inhibiteur de PAK pour les patients atteints d'un mélanome métastatique ne présentant pas de mutation du gène BRAF

Résumé en anglais

Remarkable progress has been made recently in identifying the molecular drivers of melanomagenesis. High-throughput genomic screening has revealed melanoma to be a diverse collection of tumors initiated by distinct oncogenes. About half of all cutaneous melanomas have activating mutations in the serine/threonine kinase BRAF that drives tumor initiation and progression through the mitogen-activated protein kinase (MAPK) pathway. The next most prevalent melanoma oncogene is the GTPase NRAS, which is found in 15%-20% of cases. Other histological subtypes of melanoma, such as acral lentiginous lesions arising subungually or on the palms or soles of the feet, or mucosal melanomas, tend not to harbor BRAF mutations and are sometimes dependent upon the genetic amplification of and/or activating mutations in the receptor tyrosine kinase c-KIT. Ocular melanomas lack oncogenic BRAF and are associated with deleterious mutations in the G-proteins GNAQ and GNA11. Although driving oncogenic events have been identified for approximately 70% of all cutaneous melanomas, there remains a group of approximately 30% for which the initiating event has not been determined.

In this issue of the Journal, Ong and colleagues identify p21-activating kinase 1 (PAK1) as a potential driver of and therapeutic target in a subset of BRAF wild-type (WT) melanomas. Through an initial genetic and immunohistochemical analysis, PAK1 was observed to be either amplified or overexpressed in 9% and 26% of melanomas. Segregation of the specimens on the basis of mutational status revealed those with PAK1 amplification to be BRAF WT, with no BRAF mutant tumor samples exhibiting copy number gain. When the authors considered mutational status and PAK1 protein expression, …