Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas

• Published in: Nature communications Vol. 14; no. 1; pp. 3251 - 12
• Main Authors: Liang, Jiaxin, Yu, Deyang, Luo, Chi, Bennett, Christopher, Jedrychowski, Mark, Gygi, Steve P., Widlund, Hans R., Puigserver, Pere
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 631/67; 631/67/1813; 631/67/1813/1634; 82/58; Cell Line, Tumor; Drug Collateral Sensitivity; Epigenesis, Genetic; Epigenetics; Extracellular matrix; Humanities and Social Sciences; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Inhibitors; Integrins - metabolism; Localization; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Metastases; multidisciplinary; Mutation; Neoplasm Recurrence, Local; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Science; Science (multidisciplinary); Signaling; Statins; Survival; Treatment resistance
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38968-7

While targeted treatment against BRAF(V600E) improve survival for melanoma patients, many will see their cancer recur. Here we provide data indicating that epigenetic suppression of PGC1α defines an aggressive subset of chronic BRAF-inhibitor treated melanomas. A metabolism-centered pharmacological screen further identifies statins (HMGCR inhibitors) as a collateral vulnerability within PGC1α-suppressed BRAF-inhibitor resistant melanomas. Lower PGC1α levels mechanistically causes reduced RAB6B and RAB27A expression, whereby their combined re-expression reverses statin vulnerability. BRAF-inhibitor resistant cells with reduced PGC1α have increased integrin-FAK signaling and improved extracellular matrix detached survival cues that helps explain their increased metastatic ability. Statin treatment blocks cell growth by lowering RAB6B and RAB27A prenylation that reduces their membrane association and affects integrin localization and downstream signaling required for growth. These results suggest that chronic adaptation to BRAF-targeted treatments drive novel collateral metabolic vulnerabilities, and that HMGCR inhibitors may offer a strategy to treat melanomas recurring with suppressed PGC1α expression. Melanoma phenotypic switching contributes to targeted BRAF treatment resistance. Here the authors identify a subset of BRAF treatment-resistant melanomas with suppressed PGC1a expression that are sensitive to HMGCR inhibitors.