A targetable PREX2/RAC1/PI3Kβ signalling axis confers resistance to clinically relevant therapeutic approaches in melanoma

Abstract

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identifiedbona fideactivating mutations inRAC1, with mutations of its upstream regulator, the RAC-GEFPREX2, also commonly detected. Crucially,RAC1mutations are associated with resistance to BRAF-targeting therapies. Despite the role of its homologue PREX1 in melanomagenesis, and evidence that some truncatingPREX2mutations drive increased RAC1 activity, no hotspot mutations have been identified, and the impact ofPREX2mutation remains contentious. Here, we use genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. We show that while PREX2 is dispensable for the initiation and progression of melanoma, its loss confers sensitivity to clinically relevant therapeutics. Importantly, genetic and pharmacological targeting of the RAC1 effector kinase PI3Kβ phenocopiesPREX2loss, sensitizing our model systems to therapy. Our data reveal a druggable PREX2/RAC1/PI3Kβ signalling axis inBRAF-mutant melanoma that could be exploited clinically.Statement of SignificanceMetastatic melanoma remains both a clinical problem, and an opportunity for therapeutic benefit. Co-targeting of the MAPK pathway and the PREX2/RAC1/PI3Kβ has remarkable efficacy and outperforms monotherapy MAPK targetingin vivo.