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Ref Type Journal Article
PMID (28522750)
Authors Karpel-Massler G, Ishida CT, Bianchetti E, Shu C, Perez-Lorenzo R, Horst B, Banu M, Roth KA, Bruce JN, Canoll P, Altieri DC, Siegelin MD
Title Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses.
Journal Cancer research
Vol 77
Issue 13
Date 2017 Jul 01
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown glioblastoma not applicable G-TPP + Obatoclax Preclinical - Patient cell culture Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the broad BH3 mimetic Obatoclax (GX015-070) synergistically inhibited viability of established lines and patient-derived glioblastoma cells in culture (PMID: 28522750). 28522750
Unknown unknown glioblastoma not applicable G-TPP + WEHI-539 Preclinical - Patient cell culture Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the Bcl-xL inhibitor WEHI-539 synergistically inhibited viability of established lines and patient-derived glioblastoma cells in culture (PMID: 28522750). 28522750
Unknown unknown melanoma not applicable G-TPP + WEHI-539 Preclinical - Cell culture Actionable In a preclinical study, combination of the mitochondrial Hsp90 inhibitor G-TPP and the Bcl-xL inhibitor WEHI-539 resulted in increased apoptosis of melanoma cell lines in culture (PMID: 28522750). 28522750
Unknown unknown triple-receptor negative breast cancer not applicable G-TPP + Navitoclax Preclinical - Cell line xenograft Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the broad BH3 mimetic Navitoclax (ABT-263) synergistically inhibited viability of triple-receptor negative breast cancer cells in culture, and inhibited tumor growth in cell line xenograft models (PMID: 28522750). 28522750
Unknown unknown glioblastoma not applicable A-1210477 + G-TPP Preclinical - Patient cell culture Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the Mcl-1 inhibitor A-1210477 synergistically inhibited viability of established lines and patient-derived glioblastoma cells in culture (PMID: 28522750). 28522750
Unknown unknown pancreatic cancer not applicable G-TPP + Obatoclax Preclinical - Cell culture Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the broad BH3 mimetic Obatoclax (GX015-070) synergistically inhibited viability of pancreatic cancer cells in culture (PMID: 28522750). 28522750
Unknown unknown melanoma not applicable A-1210477 + G-TPP Preclinical - Cell culture Actionable In a preclinical study, combination of the mitochondrial Hsp90 inhibitor G-TPP and the Mcl-1 inhibitor A-1210477 resulted in increased apoptosis of melanoma cell lines in culture (PMID: 28522750). 28522750
Unknown unknown pancreatic cancer not applicable G-TPP + Navitoclax Preclinical - Cell culture Actionable In a preclinical study, combination of the mitochondrial Hsp90 inhibitor G-TPP and the broad BH3 mimetic Navitoclax (ABT-263) resulted in enhanced growth inhibition of pancreatic cancer cells in culture (PMID: 28522750). 28522750
Unknown unknown melanoma not applicable G-TPP + Navitoclax Preclinical - Cell line xenograft Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the broad BH3 mimetic Navitoclax (ABT-263) synergistically inhibited viability of melanoma cell lines in culture, and inhibited tumor growth in cell line xenograft models (PMID: 28522750). 28522750
Unknown unknown triple-receptor negative breast cancer not applicable G-TPP + Obatoclax Preclinical - Cell culture Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the broad BH3 mimetic Obatoclax (GX015-070) synergistically inhibited viability of triple-receptor negative breast cancer cells in culture (PMID: 28522750). 28522750
Unknown unknown melanoma not applicable G-TPP + Obatoclax Preclinical - Cell culture Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the broad BH3 mimetic Obatoclax (GX015-070) synergistically inhibited viability of established melanoma cells in culture (PMID: 28522750). 28522750
Unknown unknown glioblastoma not applicable G-TPP + Venetoclax Preclinical - Patient cell culture Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the Bcl2 inhibitor Venclexta (venetoclax) synergistically inhibited viability of established lines and patient-derived glioblastoma cells in culture (PMID: 28522750). 28522750
Unknown unknown glioblastoma not applicable G-TPP + Navitoclax Preclinical - Pdx & cell culture Actionable In a preclinical study, the mitochondrial Hsp90 inhibitor G-TPP and the broad BH3 mimetic Navitoclax (ABT-263) synergistically inhibited viability of established lines and patient-derived glioblastoma cells in culture, and inhibited tumor growth in cell line and patient-derived xenograft models (PMID: 28522750). 28522750
Unknown unknown melanoma not applicable G-TPP + Venetoclax Preclinical - Cell culture Actionable In a preclinical study, combination of the mitochondrial Hsp90 inhibitor G-TPP and the Bcl2 inhibitor Venclexta (venetoclax) resulted in increased apoptosis of melanoma cell lines in culture (PMID: 28522750). 28522750