PMID- 35193687 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230418 IS - 2049-3002 (Print) IS - 2049-3002 (Electronic) IS - 2049-3002 (Linking) VI - 10 IP - 1 DP - 2022 Feb 22 TI - Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas. PG - 6 LID - 10.1186/s40170-022-00281-0 [doi] LID - 6 AB - BACKGROUND: Primary and posttreatment resistance to BRAF(V600) mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy. METHODS: We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)-based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment. RESULTS: A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation. CONCLUSIONS: STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas. CI - (c) 2022. The Author(s). FAU - de Groot, Evelyn AU - de Groot E AD - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. FAU - Varghese, Sruthy AU - Varghese S AD - Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. FAU - Tan, Lin AU - Tan L AD - Department of Bioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. FAU - Knighton, Barbara AU - Knighton B AD - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. FAU - Sobieski, Mary AU - Sobieski M AD - Institute of Bioscience and Technology, Texas A&M University, Houston, TX, USA. FAU - Nguyen, Nghi AU - Nguyen N AD - Institute of Bioscience and Technology, Texas A&M University, Houston, TX, USA. FAU - Park, Yong Sung AU - Park YS AD - Institute of Bioscience and Technology, Texas A&M University, Houston, TX, USA. FAU - Powell, Reid AU - Powell R AD - Institute of Bioscience and Technology, Texas A&M University, Houston, TX, USA. FAU - Lorenzi, Philip L AU - Lorenzi PL AD - Department of Bioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. FAU - Zheng, Bin AU - Zheng B AD - Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. FAU - Stephan, Clifford AU - Stephan C AD - Institute of Bioscience and Technology, Texas A&M University, Houston, TX, USA. FAU - Gopal, Y N Vashisht AU - Gopal YNV AD - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. vynanda@mdanderson.org. AD - Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. vynanda@mdanderson.org. LA - eng GR - 348483/MRA/Melanoma Research Alliance/United States GR - P30 CA016672/CA/NCI NIH HHS/United States GR - S10OD012304-01, P30CA016672/NH/NIH HHS/United States GR - CA16672, R50CA221675/CA/NCI NIH HHS/United States GR - R50 CA221675/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20220222 PL - England TA - Cancer Metab JT - Cancer & metabolism JID - 101607582 PMC - PMC8862475 OTO - NOTNLM OT - Fatty acid metabolism OT - HMGCoA reductase OT - Melanoma OT - Oxidative phosphorylation OT - Statin OT - Therapeutic resistance COIS- YNVG was funded by a research grant from Calithera Biosciences for an unrelated study. All authors declare no competing interests. EDAT- 2022/02/24 06:00 MHDA- 2022/02/24 06:01 PMCR- 2022/02/22 CRDT- 2022/02/23 05:30 PHST- 2021/08/17 00:00 [received] PHST- 2021/12/10 00:00 [accepted] PHST- 2022/02/23 05:30 [entrez] PHST- 2022/02/24 06:00 [pubmed] PHST- 2022/02/24 06:01 [medline] PHST- 2022/02/22 00:00 [pmc-release] AID - 10.1186/s40170-022-00281-0 [pii] AID - 281 [pii] AID - 10.1186/s40170-022-00281-0 [doi] PST - epublish SO - Cancer Metab. 2022 Feb 22;10(1):6. doi: 10.1186/s40170-022-00281-0.