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Adaptive mitochondrial reprogramming and resistance to PI3K therapy

Ghosh, Jagadish C; Siegelin, Markus D; Vaira, Valentina; Faversani, Alice; Tavecchio, Michele LU ; Chae, Young Chan; Lisanti, Sofia; Rampini, Paolo; Giroda, Massimo and Caino, M Cecilia, et al. (2015) In Journal of the National Cancer Institute 107(3).
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... (More)

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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@article{259ada8b-671a-4286-b353-3403b2f899d6,
  abstract     = {<p>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.</p><p>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.</p><p>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).</p><p>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.</p>},
  articleno    = {dju502},
  author       = {Ghosh, Jagadish C and Siegelin, Markus D and Vaira, Valentina and Faversani, Alice and Tavecchio, Michele and Chae, Young Chan and Lisanti, Sofia and Rampini, Paolo and Giroda, Massimo and Caino, M Cecilia and Seo, Jae Ho and Kossenkov, Andrew V and Michalek, Ryan D and Schultz, David C and Bosari, Silvano and Languino, Lucia R and Altieri, Dario C},
  issn         = {1460-2105},
  keyword      = {Animals,Antineoplastic Agents,Apoptosis,Brain Neoplasms,Cell Line, Tumor,Cell Survival,Cellular Reprogramming,Cyclophilins,Drug Resistance, Neoplasm,Drug Synergism,Elafin,Energy Metabolism,Glioblastoma,Guanidines,Humans,Immunocompromised Host,Mice,Mitochondria,Phosphorylation,Protein Folding,Proto-Oncogene Proteins c-akt,Xenograft Model Antitumor Assays,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't,Research Support, U.S. Gov't, Non-P.H.S.},
  language     = {eng},
  number       = {3},
  publisher    = {Oxford University Press},
  series       = {Journal of the National Cancer Institute},
  title        = {Adaptive mitochondrial reprogramming and resistance to PI3K therapy},
  url          = {http://dx.doi.org/10.1093/jnci/dju502},
  volume       = {107},
  year         = {2015},
}