| Autor: |
Ford CA; Cancer Research UK Beatson Institute, Glasgow, Scotland, United Kingdom., Koludrovic D; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Centeno PP; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Foth M; University of Utah, Salt Lake City, UT, United States., Tsonou E; Babraham Institute, United Kingdom., Vlahov N; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Sphyris N; Cancer Research UK Scotland Institute, Glasgow, Scotland, United Kingdom., Gilroy K; Beatson Institute for Cancer Research, Glasgow, United Kingdom., Bull C; Queen's University Belfast, Belfast, United Kingdom., Nixon C; CRUK Scotland Institute, Glasgow, United Kingdom., Serrels B; University of Edinburgh, Edinburgh, Scotland, United Kingdom., Munro AF; University of Edinburgh, Edinburgh, United Kingdom., Dawson JC; University of Edinburgh, Edinburgh, Scotland, United Kingdom., Carragher NO; University of Edinburgh, Edinburgh, Scotland, United Kingdom., Pavet V; The Beatson Institute for Cancer Research, Glasgow, United Kingdom., Hornigold DC; AstraZeneca (United Kingdom), Cambridge, United Kingdom., Dunne PD; Queen's University Belfast, Belfast, United Kingdom., Downward J; The Francis Crick Institute, London, United Kingdom., Welch HC; Babraham Institute, United Kingdom., Barry ST; AstraZeneca (United Kingdom), Cambridge, United Kingdom., Sansom OJ; CRUK Beatson Institute, Glasgow, United Kingdom., Campbell AD; Cancer Research UK Beatson Institute, Glasgow, United Kingdom. |
| Abstrakt: |
Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression. Here, we used genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. While PREX2 was dispensable for the initiation and progression of melanoma, its loss conferred sensitivity to clinically relevant therapeutics targeting the MAPK pathway. Importantly, genetic and pharmacological targeting of PI3Kβ phenocopied PREX2 deficiency, sensitizing model systems to therapy. These data reveal a druggable PREX2/RAC1/PI3Kβ signaling axis in BRAF-mutant melanoma that could be exploited clinically. |
