PMID- 32430489 OWN - NLM STAT- MEDLINE DCOM- 20210602 LR - 20210929 IS - 1538-8514 (Electronic) IS - 1535-7163 (Print) IS - 1535-7163 (Linking) VI - 19 IP - 8 DP - 2020 Aug TI - Metabolic Adaptations to MEK and CDK4/6 Cotargeting in Uveal Melanoma. PG - 1719-1726 LID - 10.1158/1535-7163.MCT-19-1016 [doi] AB - Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK-ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) and cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in patients with estrogen receptor (ER)-positive breast cancer in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in uveal melanoma. In vitro, palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell-cycle proteins. In contrast, in vivo CDK4/6 inhibition alone led to cytostasis and was as effective as MEKi plus CDK4/6i treatment at delaying tumor growth. RNA sequencing revealed upregulation of the oxidative phosphorylation (OxPhos) pathway in both MEKi-resistant tumors and CDK4/6i-tolerant tumors. Furthermore, oxygen consumption rate was increased following MEKi + CDK4/6i treatment. IACS-010759, an OxPhos inhibitor, decreased uveal melanoma cell survival in combination with MEKi + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations. CI - (c)2020 American Association for Cancer Research. FAU - Teh, Jessica L F AU - Teh JLF AUID- ORCID: 0000-0003-1841-671X AD - Department of Cancer Biology, Philadelphia, Pennsylvania. FAU - Purwin, Timothy J AU - Purwin TJ AUID- ORCID: 0000-0002-7053-8039 AD - Department of Cancer Biology, Philadelphia, Pennsylvania. FAU - Han, Anna AU - Han A AUID- ORCID: 0000-0001-8180-6214 AD - Department of Cancer Biology, Philadelphia, Pennsylvania. FAU - Chua, Vivian AU - Chua V AUID- ORCID: 0000-0002-1873-6820 AD - Department of Cancer Biology, Philadelphia, Pennsylvania. FAU - Patel, Prem AU - Patel P AD - Department of Cancer Biology, Philadelphia, Pennsylvania. FAU - Baqai, Usman AU - Baqai U AD - Department of Cancer Biology, Philadelphia, Pennsylvania. FAU - Liao, Connie AU - Liao C AD - Department of Cancer Biology, Philadelphia, Pennsylvania. FAU - Bechtel, Nelisa AU - Bechtel N AD - Department of Cancer Biology, Philadelphia, Pennsylvania. FAU - Sato, Takami AU - Sato T AUID- ORCID: 0000-0003-2221-0415 AD - Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. AD - Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania. FAU - Davies, Michael A AU - Davies MA AUID- ORCID: 0000-0002-0977-0912 AD - Department of Melanoma Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas. FAU - Aguirre-Ghiso, Julio AU - Aguirre-Ghiso J AD - Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. AD - Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York. AD - Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. FAU - Aplin, Andrew E AU - Aplin AE AUID- ORCID: 0000-0002-2734-3244 AD - Department of Cancer Biology, Philadelphia, Pennsylvania. Andrew.Aplin@Jefferson.edu. AD - Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - P30 CA056036/CA/NCI NIH HHS/United States GR - R01 CA182635/CA/NCI NIH HHS/United States GR - T32 CA009666/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200519 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (Benzamides) RN - 0 (Biomarkers, Tumor) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridones) RN - 0 (Pyrimidinones) RN - 33E86K87QN (trametinib) RN - 86K0J5AK6M (mirdametinib) RN - 9N3CBB0BIQ (Diphenylamine) RN - EC 2.7.11.22 (CDK4 protein, human) RN - EC 2.7.11.22 (CDK6 protein, human) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 4) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 6) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - EC 2.7.12.2 (MAP2K1 protein, human) RN - Uveal melanoma SB - IM MH - Animals MH - Apoptosis MH - Benzamides/pharmacology MH - Biomarkers, Tumor/genetics/metabolism MH - Cell Proliferation MH - Cyclin-Dependent Kinase 4/*antagonists & inhibitors MH - Cyclin-Dependent Kinase 6/*antagonists & inhibitors MH - Diphenylamine/analogs & derivatives/pharmacology MH - Female MH - Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic/*drug effects MH - Humans MH - MAP Kinase Kinase 1/*antagonists & inhibitors MH - Melanoma/*drug therapy/metabolism/pathology MH - Mice MH - Mice, Nude MH - Oxidative Phosphorylation MH - Oxygen Consumption MH - Protein Kinase Inhibitors/*pharmacology MH - Pyridones/pharmacology MH - Pyrimidinones/pharmacology MH - Transcriptome/*drug effects MH - Tumor Cells, Cultured MH - Uveal Neoplasms/*drug therapy/metabolism/pathology MH - Xenograft Model Antitumor Assays PMC - PMC7415561 MID - NIHMS1597331 EDAT- 2020/05/21 06:00 MHDA- 2021/06/03 06:00 PMCR- 2021/02/01 CRDT- 2020/05/21 06:00 PHST- 2019/10/25 00:00 [received] PHST- 2020/03/19 00:00 [revised] PHST- 2020/05/15 00:00 [accepted] PHST- 2020/05/21 06:00 [pubmed] PHST- 2021/06/03 06:00 [medline] PHST- 2020/05/21 06:00 [entrez] PHST- 2021/02/01 00:00 [pmc-release] AID - 1535-7163.MCT-19-1016 [pii] AID - 10.1158/1535-7163.MCT-19-1016 [doi] PST - ppublish SO - Mol Cancer Ther. 2020 Aug;19(8):1719-1726. doi: 10.1158/1535-7163.MCT-19-1016. Epub 2020 May 19.