Adaptive mitochondrial reprogramming and resistance to PI3K therapy

Jagadish C. Ghosh, Markus D. Siegelin, Valentina Vaira, Alice Faversani, Michele Tavecchio, Young Chan Chae, Sofia Lisanti, Paolo Rampini, Massimo Giroda, M. Cecilia Caino, Jae Ho Seo, Andrew V. Kossenkov, Ryan D. Michalek, David C. Schultz, Silvano Bosari, Lucia R. Languino, Dario C. Altieri

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numberdju502
JournalJournal of the National Cancer Institute
Volume107
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

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Phosphatidylinositol 3-Kinase
Glioblastoma
Energy Metabolism
Therapeutics
Survival
Neoplasms
Phosphatidylinositol 3-Kinases
Cell Death
Drug Repositioning
Preclinical Drug Evaluations
Metabolomics
Protein Folding
Tumor Cell Line
Drug Resistance
Organelles
Cell Survival
Mitochondria
Phosphotransferases
Phosphorylation
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Adaptive mitochondrial reprogramming and resistance to PI3K therapy. / Ghosh, Jagadish C.; Siegelin, Markus D.; Vaira, Valentina; Faversani, Alice; Tavecchio, Michele; Chae, Young Chan; Lisanti, Sofia; Rampini, Paolo; Giroda, Massimo; Caino, M. Cecilia; Seo, Jae Ho; Kossenkov, Andrew V.; Michalek, Ryan D.; Schultz, David C.; Bosari, Silvano; Languino, Lucia R.; Altieri, Dario C.

In: Journal of the National Cancer Institute, Vol. 107, No. 3, dju502, 01.03.2015.

Research output: Contribution to journalArticle

Ghosh, JC, Siegelin, MD, Vaira, V, Faversani, A, Tavecchio, M, Chae, YC, Lisanti, S, Rampini, P, Giroda, M, Caino, MC, Seo, JH, Kossenkov, AV, Michalek, RD, Schultz, DC, Bosari, S, Languino, LR & Altieri, DC 2015, 'Adaptive mitochondrial reprogramming and resistance to PI3K therapy', Journal of the National Cancer Institute, vol. 107, no. 3, dju502. https://doi.org/10.1093/jnci/dju502
Ghosh, Jagadish C. ; Siegelin, Markus D. ; Vaira, Valentina ; Faversani, Alice ; Tavecchio, Michele ; Chae, Young Chan ; Lisanti, Sofia ; Rampini, Paolo ; Giroda, Massimo ; Caino, M. Cecilia ; Seo, Jae Ho ; Kossenkov, Andrew V. ; Michalek, Ryan D. ; Schultz, David C. ; Bosari, Silvano ; Languino, Lucia R. ; Altieri, Dario C. / Adaptive mitochondrial reprogramming and resistance to PI3K therapy. In: Journal of the National Cancer Institute. 2015 ; Vol. 107, No. 3.
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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.",
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AU - Siegelin, Markus D.

AU - Vaira, Valentina

AU - Faversani, Alice

AU - Tavecchio, Michele

AU - Chae, Young Chan

AU - Lisanti, Sofia

AU - Rampini, Paolo

AU - Giroda, Massimo

AU - Caino, M. Cecilia

AU - Seo, Jae Ho

AU - Kossenkov, Andrew V.

AU - Michalek, Ryan D.

AU - Schultz, David C.

AU - Bosari, Silvano

AU - Languino, Lucia R.

AU - Altieri, Dario C.

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N2 - 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.

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