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Theranostics 2021; 11(11):5127-5142. doi:10.7150/thno.54741 This issue Cite

Research Paper

Kinomic profile in patient-derived glioma cells during hypoxia reveals c-MET-PI3K dependency for adaptation

Hong Sheng Cheng^1,2✉, Charlie Marvalim¹, Pengcheng Zhu¹, Cheng Lui Daniel Law¹, Zhi Yan Jeremy Low¹, Yuk Kien Chong³, Beng Ti Ang^4,5,6, Carol Tang^1,3,5, Nguan Soon Tan^1,2✉

1. School of Biological Sciences, Nanyang Technological University Singapore, Singapore 637551, Singapore.
2. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore.
3. Neuro-Oncology Research Laboratory, Department of Research, National Neuroscience Institute, Singapore 308433, Singapore.
4. Department of Neurosurgery, National Neuroscience Institute, Singapore 308433, Singapore.
5. Duke-National University of Singapore Medical School, Singapore 169857, Singapore.
6. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.

✉ Corresponding authors: H.S.C. E-mail: hschengedu.sg; N.S.T. (senior corresponding author) E-mail: nstanedu.sg; Tel: (65) 6904 1295; Fax: (65) 6339 2889.

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.

Keywords: glioblastoma, HIF-1α, oxidative stress, PI3K, tumor microenvironment

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