Jagadish C Ghosh1, Markus D Siegelin1, Valentina Vaira1, Alice Faversani1, Michele Tavecchio1, Young Chan Chae1, Sofia Lisanti1, Paolo Rampini1, Massimo Giroda1, M Cecilia Caino1, Jae Ho Seo1, Andrew V Kossenkov1, Ryan D Michalek1, David C Schultz1, Silvano Bosari1, Lucia R Languino1, Dario C Altieri2. 1. Prostate Cancer Discovery and Development Program (JCG, MT, YCC, SL, MCC, JHS, LRL, DCA), Tumor Microenvironment and Metastasis Program (JCG, MT, YCC, SL, MCC, JHS, DCA), Center for Systems and Computational Biology (AVK), and Center for Chemical Biology and Translational Medicine (DCS), The Wistar Institute, Philadelphia, PA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY (MDS); Istituto Nazionale Genetica Molecolare "Romeo and Enrica Invernizzi," Milan, Italy (VV); Division of Pathology (VV, AF, SB), Division of Neurosurgery (PR), and Division of Surgery (MG), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Metabolon, Inc. Durham, NC (RDM); Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy (SB); Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (LRL). 2. Prostate Cancer Discovery and Development Program (JCG, MT, YCC, SL, MCC, JHS, LRL, DCA), Tumor Microenvironment and Metastasis Program (JCG, MT, YCC, SL, MCC, JHS, DCA), Center for Systems and Computational Biology (AVK), and Center for Chemical Biology and Translational Medicine (DCS), The Wistar Institute, Philadelphia, PA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY (MDS); Istituto Nazionale Genetica Molecolare "Romeo and Enrica Invernizzi," Milan, Italy (VV); Division of Pathology (VV, AF, SB), Division of Neurosurgery (PR), and Division of Surgery (MG), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Metabolon, Inc. Durham, NC (RDM); Department of Pathophysiology and Organ Transplant, University of Milan, Milan, Italy (SB); Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (LRL). daltieri@wistar.org.
Abstract
BACKGROUND: Small molecule inhibitors of phosphatidylinositol-3 kinase (PI3K) have been developed as molecular therapy for cancer, but their efficacy in the clinic is modest, hampered by resistance mechanisms. METHODS: We studied the effect of PI3K therapy in patient-derived tumor organotypic cultures (from five patient samples), three glioblastoma (GBM) tumor cell lines, and an intracranial model of glioblastoma in immunocompromised mice (n = 4-5 mice per group). Mechanisms of therapy-induced tumor reprogramming were investigated in a global metabolomics screening, analysis of mitochondrial bioenergetics and cell death, and modulation of protein phosphorylation. A high-throughput drug screening was used to identify novel preclinical combination therapies with PI3K inhibitors, and combination synergy experiments were performed. All statistical methods were two-sided. RESULTS: PI3K therapy induces global metabolic reprogramming in tumors and promotes the recruitment of an active pool of the Ser/Thr kinase, Akt2 to mitochondria. In turn, mitochondrial Akt2 phosphorylates Ser31 in cyclophilin D (CypD), a regulator of organelle functions. Akt2-phosphorylated CypD supports mitochondrial bioenergetics and opposes tumor cell death, conferring resistance to PI3K therapy. The combination of a small-molecule antagonist of CypD protein folding currently in preclinical development, Gamitrinib, plus PI3K inhibitors (PI3Ki) reverses this adaptive response, produces synergistic anticancer activity by inducing mitochondrial apoptosis, and extends animal survival in a GBM model (vehicle: median survival = 28.5 days; Gamitrinib+PI3Ki: median survival = 40 days, P = .003), compared with single-agent treatment (PI3Ki: median survival = 32 days, P = .02; Gamitrinib: median survival = 35 days, P = .008 by two-sided unpaired t test). CONCLUSIONS: Small-molecule PI3K antagonists promote drug resistance by repurposing mitochondrial functions in bioenergetics and cell survival. Novel combination therapies that target mitochondrial adaptation can dramatically improve on the efficacy of PI3K therapy in the clinic.
BACKGROUND: Small molecule inhibitors of phosphatidylinositol-3 kinase (PI3K) have been developed as molecular therapy for cancer, but their efficacy in the clinic is modest, hampered by resistance mechanisms. METHODS: We studied the effect of PI3K therapy in patient-derived tumor organotypic cultures (from five patient samples), three glioblastoma (GBM) tumor cell lines, and an intracranial model of glioblastoma in immunocompromised mice (n = 4-5 mice per group). Mechanisms of therapy-induced tumor reprogramming were investigated in a global metabolomics screening, analysis of mitochondrial bioenergetics and cell death, and modulation of protein phosphorylation. A high-throughput drug screening was used to identify novel preclinical combination therapies with PI3K inhibitors, and combination synergy experiments were performed. All statistical methods were two-sided. RESULTS: PI3K therapy induces global metabolic reprogramming in tumors and promotes the recruitment of an active pool of the Ser/Thr kinase, Akt2 to mitochondria. In turn, mitochondrial Akt2 phosphorylates Ser31 in cyclophilin D (CypD), a regulator of organelle functions. Akt2-phosphorylated CypD supports mitochondrial bioenergetics and opposes tumor cell death, conferring resistance to PI3K therapy. The combination of a small-molecule antagonist of CypD protein folding currently in preclinical development, Gamitrinib, plus PI3K inhibitors (PI3Ki) reverses this adaptive response, produces synergistic anticancer activity by inducing mitochondrial apoptosis, and extends animal survival in a GBM model (vehicle: median survival = 28.5 days; Gamitrinib+PI3Ki: median survival = 40 days, P = .003), compared with single-agent treatment (PI3Ki: median survival = 32 days, P = .02; Gamitrinib: median survival = 35 days, P = .008 by two-sided unpaired t test). CONCLUSIONS: Small-molecule PI3K antagonists promote drug resistance by repurposing mitochondrial functions in bioenergetics and cell survival. Novel combination therapies that target mitochondrial adaptation can dramatically improve on the efficacy of PI3K therapy in the clinic.
Authors: V Serra; M Scaltriti; L Prudkin; P J A Eichhorn; Y H Ibrahim; S Chandarlapaty; B Markman; O Rodriguez; M Guzman; S Rodriguez; M Gili; M Russillo; J L Parra; S Singh; J Arribas; N Rosen; J Baselga Journal: Oncogene Date: 2011-01-31 Impact factor: 9.867
Authors: Andrew J Armstrong; Susan Halabi; Patrick Healy; Joshi J Alumkal; Carolyn Winters; Julie Kephart; Rhonda L Bitting; Carey Hobbs; Colleen F Soleau; Tomasz M Beer; Rachel Slottke; Kelly Mundy; Evan Y Yu; Daniel J George Journal: Eur J Cancer Date: 2017-05-11 Impact factor: 9.162
Authors: Yiru Zhang; Trang T T Nguyen; Enyuan Shang; Angeliki Mela; Nelson Humala; Aayushi Mahajan; Junfei Zhao; Chang Shu; Consuelo Torrini; Maria J Sanchez-Quintero; Giulio Kleiner; Elena Bianchetti; Mike-Andrew Westhoff; Catarina M Quinzii; Georg Karpel-Massler; Jeffrey N Bruce; Peter Canoll; Markus D Siegelin Journal: Cancer Res Date: 2019-11-06 Impact factor: 12.701
Authors: Chiaki T Ishida; Yiru Zhang; Elena Bianchetti; Chang Shu; Trang T T Nguyen; Giulio Kleiner; Maria J Sanchez-Quintero; Catarina M Quinzii; Mike-Andrew Westhoff; Georg Karpel-Massler; Varun V Prabhu; Joshua E Allen; Markus D Siegelin Journal: Clin Cancer Res Date: 2018-07-23 Impact factor: 12.531
Authors: Francesca Ricci; Alessandro Corbelli; Roberta Affatato; Rosaria Chilà; Michela Chiappa; Laura Brunelli; Robert Fruscio; Roberta Pastorelli; Fabio Fiordaliso; Giovanna Damia Journal: Am J Cancer Res Date: 2021-05-15 Impact factor: 6.166