title: Adaptive mitochondrial reprogramming and resistance to PI3K therapy.
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.
authors: 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).
authors: Jagadish C
authors: JC
authors: Ghosh
authors: 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).
authors: Markus D
authors: MD
authors: Siegelin
authors: 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).
authors: Valentina
authors: V
authors: Vaira
authors: 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).
authors: Alice
authors: A
authors: Faversani
authors: 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).
authors: Michele
authors: M
authors: Tavecchio
authors: 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).
authors: Young Chan
authors: YC
authors: Chae
authors: 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).
authors: Sofia
authors: S
authors: Lisanti
authors: 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).
authors: Paolo
authors: P
authors: Rampini
authors: 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).
authors: Massimo
authors: M
authors: Giroda
authors: 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).
authors: M Cecilia
authors: MC
authors: Caino
authors: 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).
authors: Jae Ho
authors: JH
authors: Seo
authors: 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).
authors: Andrew V
authors: AV
authors: Kossenkov
authors: 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).
authors: Ryan D
authors: RD
authors: Michalek
authors: 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).
authors: David C
authors: DC
authors: Schultz
authors: 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).
authors: Silvano
authors: S
authors: Bosari
authors: 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).
authors: Lucia R
authors: LR
authors: Languino
authors: 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.
authors: Dario C
authors: DC
authors: Altieri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D065150:Cellular Reprogramming; D021983:Cyclophilins / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D053492:Elafin / Q000037:antagonists & inhibitors*; D004734:Energy Metabolism / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D016867:Immunocompromised Host; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097322:Peptidyl-Prolyl Isomerase D
chemical_list: D000970:Antineoplastic Agents; D021983:Cyclophilins; D053492:Elafin; D006146:Guanidines; D051057:Proto-Oncogene Proteins c-akt; C506806:PI3 protein, human; C494921:AKT2 protein, human; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D
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