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Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas

Version 2 2024-06-13, 16:15
Version 1 2022-10-26, 22:38
journal contribution
posted on 2024-06-13, 16:15 authored by S Wei, D Yin, S Yu, X Lin, MR Savani, K Du, Y Ku, D Wu, S Li, H Liu, M Tian, Y Chen, M Bowie, S Hariharan, M Waitkus, ST Keir, ET Sugarman, RA Deek, M Labrie, M Khasraw, Y Lu, GB Mills, M Herlyn, K Wu, L Liu, Z Wei, KT Flaherty, K Abdullah, G Zhang, DM Ashley
Purpose: To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas. Experimental Design: A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line–derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib. Results: Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response. Conclusions: These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.

History

Journal

Clinical Cancer Research

Volume

28

Pagination

2180-2195

Location

Philadelphia, Pa.

ISSN

1078-0432

eISSN

1557-3265

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Issue

10

Publisher

American Association for Cancer Research

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