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Therapeutics, Targets, and Chemical Biology

Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses

Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A. Roth, Jeffrey N. Bruce, Peter Canoll, Dario C. Altieri and Markus D. Siegelin
Georg Karpel-Massler
Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
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Chiaki Tsuge Ishida
Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
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Elena Bianchetti
Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
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Chang Shu
Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
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Rolando Perez-Lorenzo
Department of Dermatology, Columbia University Medical Center, New York, New York.
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Basil Horst
Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.Department of Dermatology, Columbia University Medical Center, New York, New York.
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Matei Banu
Department of Neurosurgery, Columbia University Medical Center, New York, New York.
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Kevin A. Roth
Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
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Jeffrey N. Bruce
Department of Neurosurgery, Columbia University Medical Center, New York, New York.
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Peter Canoll
Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
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Dario C. Altieri
The Wistar Institute, Philadelphia, Pennsylvania.
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Markus D. Siegelin
Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.
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  • For correspondence: ms4169@cumc.columbia.edu
DOI: 10.1158/0008-5472.CAN-16-3424 Published July 2017
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Abstract

Rational therapeutic approaches based on synthetic lethality may improve cancer management. On the basis of a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL, and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and obatoclax) or selective (ABT199, WEHI-539, and A1210477), along with the established mitochondrial matrix chaperone inhibitor gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer, and patient-derived orthotopic xenografts (PDX) of human glioblastoma. We found that combining BH3 mimetics and gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL, or Mcl-1 recapitulated the effects of BH3 mimetics and enhanced the effects of gamitrinib-TPP. Mechanistic investigations revealed that gamitrinib-TPP activated a PERK-dependent integrated stress response, which activated the proapoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments. Cancer Res; 77(13); 3513–26. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received December 22, 2016.
  • Revision received March 22, 2017.
  • Accepted April 28, 2017.
  • ©2017 American Association for Cancer Research.
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Cancer Research: 77 (13)
July 2017
Volume 77, Issue 13
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Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A. Roth, Jeffrey N. Bruce, Peter Canoll, Dario C. Altieri and Markus D. Siegelin
Cancer Res July 1 2017 (77) (13) 3513-3526; DOI: 10.1158/0008-5472.CAN-16-3424

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Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A. Roth, Jeffrey N. Bruce, Peter Canoll, Dario C. Altieri and Markus D. Siegelin
Cancer Res July 1 2017 (77) (13) 3513-3526; DOI: 10.1158/0008-5472.CAN-16-3424
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