An inhibitor of oxidative phosphorylation exploits cancer vulnerability.

Autor: Molina JR; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Sun Y; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Protopopova M; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gera S; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bandi M; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bristow C; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., McAfoos T; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Morlacchi P; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Agilent Technologies Inc., Lexington, MA, USA., Ackroyd J; Department of Cancer Imaging Systems, University of Texas MD Cancer Center, Houston, TX, USA., Agip AA; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, UK., Al-Atrash G; Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Asara J; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Bardenhagen J; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Carrillo CC; Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Carroll C; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Chang E; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ciurea S; Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Cross JB; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Czako B; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Deem A; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Daver N; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA., de Groot JF; Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Dong JW; Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Feng N; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gao G; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gay J; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Do MG; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Greer J; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Giuliani V; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Han J; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Han L; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Henry VK; Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hirst J; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, UK., Huang S; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jiang Y; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kang Z; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Khor T; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Konoplev S; Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lin YH; Department of Cancer Imaging Systems, University of Texas MD Cancer Center, Houston, TX, USA., Liu G; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lodi A; Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA., Lofton T; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ma H; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Mahendra M; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Matre P; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Mullinax R; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Peoples M; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Petrocchi A; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Rodriguez-Canale J; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Serreli R; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Cambridge, UK., Shi T; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Smith M; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Tabe Y; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Next Generation Hematology Laboratory Medicine, Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan., Theroff J; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Tiziani S; Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA., Xu Q; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Zhang Q; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Muller F; Department of Cancer Imaging Systems, University of Texas MD Cancer Center, Houston, TX, USA., DePinho RA; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Toniatti C; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Draetta GF; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Heffernan TP; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Konopleva M; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jones P; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Di Francesco ME; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Marszalek JR; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA. jrmarszalek@mdanderson.org.; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA. jrmarszalek@mdanderson.org.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2018 Jul; Vol. 24 (7), pp. 1036-1046. Date of Electronic Publication: 2018 Jun 11.
DOI: 10.1038/s41591-018-0052-4
Abstrakt: Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.
Databáze: MEDLINE
Externí odkaz: