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

Cancer Research
Georg Karpel-MasslerMarkus D Siegelin

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 proapop...Continue Reading

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Citations

Jul 18, 2017·Expert Opinion on Drug Discovery·Georg Karpel-MasslerMarkus D Siegelin
Aug 31, 2019·EMBO Molecular Medicine·Trang Thi Thu NguyenMarkus D Siegelin
Nov 28, 2018·Scientific Reports·E BianchettiK A Roth
Feb 9, 2018·Oncotarget·Georg Karpel-MasslerMarkus D Siegelin
Sep 12, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yu-Cheng ChouJing-Gung Chung
Nov 27, 2019·CNS Drugs·Georg Karpel-MasslerMarkus D Siegelin
Apr 22, 2020·The Journal of Clinical Investigation·Trang Thi Thu NguyenMarkus D Siegelin
Oct 24, 2017·Nature Communications·Georg Karpel-MasslerMarkus D Siegelin
Apr 26, 2019·Cell Death & Disease·Erinna F LeeW Douglas Fairlie
Jun 13, 2020·Frontiers in Oncology·Angelica AvaglianoAlessandro Arcucci
Oct 20, 2018·Scientific Reports·Enyuan ShangMarkus D Siegelin
Jul 25, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Chiaki T IshidaMarkus D Siegelin
May 17, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Yiru ZhangMarkus D Siegelin
Feb 16, 2021·Frontiers in Oncology·Ricardo Gómez-OlivaNoelia Geribaldi-Doldán
Dec 17, 2020·Journal of Microbiology and Biotechnology·Zhen FanBo Yang
Apr 4, 2021·International Journal of Molecular Sciences·Anna Maria LucianòDonatella Del Bufalo
May 7, 2021·International Journal of Pharmaceutics·Yuanyuan ChenJian Ming

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