Anti-tumor Activity of a Mitochondrial Targeted HSP90 Inhibitor in Gliomas.

To investigate the anti-tumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the anti-tumor mechanisms of Gamitrinib in gliomas.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 anti-tumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDOs), cell line-derived xenografts (CDX) and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib.Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cells, 6 TMZ-resistant glioma cells, 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 anti-tumor activity via (1) suppressing mitochondrial biogenesis, OXPHOS and cell cycle progression and (2) activating the energy-sensing AMP-activated kinase, DNA damage and stress response.These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary anti-tumor mechanisms in gliomas.