A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress.

in Scientific reports by Joshua L Katz, Yuheng Geng, Leah K Billingham, Nishanth S Sadagopan, Susan L DeLay, Jay Subbiah, Tzu-Yi Chia, Graysen McManus, Chao Wei, Hanxiang Wang, Hanchen Lin, Caylee Silvers, Lauren K Boland, Si Wang, Hanxiao Wan, David Hou, Gustavo Ignacio Vázquez-Cervantes, Tarlan Arjmandi, Zainab H Shaikh, Peng Zhang, Atique U Ahmed, Deanna M Tiek, Catalina Lee-Chang, Edward T Chouchani, Jason Miska

TLDR

  • The study found that a drug called CKi can stop Glioblastoma (GBM) cells from moving around in the brain. The drug also stopped the cells from invading other parts of the brain. The study also found that the drug affects the way the cells make a chemical called glutathione, which helps protect the cells from damage. The study suggests that the drug could be used to treat GBM.

Abstract

Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.

Overview

  • The study explores the role of a creatine kinase inhibitor (CKi) on Glioblastoma (GBM) biology in vitro. The hypothesis being tested is whether CKi impacts GBM cell proliferation, viability, migration, and invasion. The methodology used for the experiment includes the use of established GBM cell lines and patient-derived xenografts, as well as RNA-seq and carbon-13 metabolite tracing. The primary objective of the study is to identify the creatine kinase axis as a druggable target for GBM treatment.

Comparative Analysis & Findings

  • The study found that CKi minimally impacted GBM cell proliferation and viability but significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival.

Implications and Future Directions

  • The study's findings suggest that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment. Future research directions could include the development of CKi-based therapies for GBM, the exploration of the role of glutathione metabolism and ferroptosis in GBM, and the investigation of the combination of CKi blockade and other therapies for GBM treatment.
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