Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/153593
Title: Kinomic profile in patient-derived glioma cells during hypoxia reveals c-MET-PI3K dependency for adaptation
Authors: Cheng, Hong Sheng
Marvalim, Charlie
Zhu, Pengcheng
Law, Daniel Cheng Lui
Low, Jeremy Zhi Yan
Chong, Yuk Kien
Ang, Beng Ti
Tang, Carol
Tan, Nguan Soon
Keywords: Science::Medicine
Issue Date: 2021
Source: Cheng, H. S., Marvalim, C., Zhu, P., Law, D. C. L., Low, J. Z. Y., Chong, Y. K., Ang, B. T., Tang, C. & Tan, N. S. (2021). Kinomic profile in patient-derived glioma cells during hypoxia reveals c-MET-PI3K dependency for adaptation. Theranostics, 11(11), 5127-5142. https://dx.doi.org/10.7150/thno.54741
Project: NMRC/ TCR/016-NNI/2016
Journal: Theranostics
Abstract: Hypoxic microenvironment is a hallmark of solid tumors, especially glioblastoma. The strong reliance of glioma-propagating cells (GPCs) on hypoxia-induced survival advantages is potentially exploitable for drug development. Methods: To identify key signaling pathways for hypoxia adaptation by patient-derived GPCs, we performed a kinase inhibitor profiling by screening 188 small molecule inhibitors against 130 different kinases in normoxia and hypoxia. Potential kinase candidates were prioritized for in vitro and in vivo investigations using a ranking algorithm that integrated information from the kinome connectivity network and estimated patients' survival based on expression status. Results: Hypoxic drug screen highlighted extensive modifications of kinomic landscape and a crucial functionality of c-MET-PI3K. c-MET inhibitors diminished phosphorylation of c-MET and PI3K in GPCs subjected to hypoxia, suggesting its role in the hypoxic adaptation of GPCs. Mechanistically, the inhibition of c-MET and PI3K impaired antioxidant defense, leading to oxidative catastrophe and apoptosis. Repurposed c-MET inhibitors PF04217903 and tivantinib exhibited hypoxic-dependent drug synergism with temozolomide, resulting in reduced tumor load and growth of GPC xenografts. Detailed analysis of bulk and single-cell glioblastoma transcriptomes associates the cellular subpopulation over-expressing c-MET with inflamed, hypoxic, metastatic, and stem-like phenotypes. Conclusions: Thus, our "bench to bedside (the use of patient-derived GPCs and xenografts for basic research) and back (validation with independent glioblastoma transcriptome databases)" analysis unravels the novel therapeutic indications of c-MET and PI3K/Akt inhibitors for the treatment of glioblastoma, and potentially other cancers, in the hypoxic tumor microenvironment.
URI: https://hdl.handle.net/10356/153593
ISSN: 1838-7640
DOI: 10.7150/thno.54741
Rights: © 2021 The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
SBS Journal Articles

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