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

Extract

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 ( 1 ). 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 ( 2 ). 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 ( 3 ). 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.