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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 | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 |