Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas

Author:

Wei Shiyou123,Yin Delong234ORCID,Yu Shengnan235,Lin Xiang6ORCID,Savani Milan R.7ORCID,Du Kuang6,Ku Yin1,Wu Di1,Li Shasha1,Liu Hao8,Tian Meng89,Chen Yaohui1,Bowie Michelle23,Hariharan Seethalakshmi23,Waitkus Matthew23ORCID,Keir Stephen T.23,Sugarman Eric T.10,Deek Rebecca A.11,Labrie Marilyne12,Khasraw Mustafa23ORCID,Lu Yiling13,Mills Gordon B.12ORCID,Herlyn Meenhard14,Wu Kongming15,Liu Lunxu1ORCID,Wei Zhi6ORCID,Flaherty Keith T.16,Abdullah Kalil7ORCID,Zhang Gao2317ORCID,Ashley David M.23

Affiliation:

1. Department of Thoracic Surgery, Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

2. The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.

3. Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina.

4. Department of Orthopedics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.

5. Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

6. Department of Computer Science, Ying Wu College of Computing, New Jersey Institute of Technology, Newark, New Jersey.

7. Department of Neurosurgery, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.

8. Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

9. Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

10. Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania.

11. Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

12. Knight Cancer Institute, Oregon Health Sciences University, Portland, Oregon.

13. Division of Cancer Medicine, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

14. The Wistar Institute, Philadelphia, Pennsylvania.

15. Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

16. Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

17. Department of Pathology, Duke University School of Medicine, Durham, North Carolina.

Abstract

Abstract 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.

Funder

National Natural Science Foundation of China

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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