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Systematic screening identifies dual PI3K and mTOR inhibition as a conserved therapeutic vulnerability in osteosarcoma


Gupte, A; Baker, E; Wan, SS; Stewart, E; Loh, A; Shelat, AA; Gould, CM; Chalk, A; Taylor, S; Lackovic, K; Karlstrom, A; Mutsaers, A; Desai, J; Madhamshettiwar, PB; Zannettino, AC; Burns, C; Huang, DC; Dyer, M; Simpson, KJ; Walkley, C
2015-04-10
Clinical Cancer Research
Journal Article
21
14
3216-3229
PURPOSE: Osteosarcoma (OS) is the most common cancer of bone occurring mostly in teenagers. Despite rapid advances in our knowledge of the genetics and cell biology of OS, significant improvements in patient survival have not been observed. The identification of effective therapeutics has been largely empirically based. The identification of new therapies and therapeutic targets are urgently needed to enable improved outcomes for OS patients. EXPERIMENTAL DESIGN: We have used genetically engineered murine models of human OS in a systematic, genome wide screen to identify new candidate therapeutic targets. We performed a genome wide siRNA screen, with or without doxorubicin. In parallel a screen of therapeutically relevant small molecules was conducted on primary murine and primary human OS derived cell cultures. All results were validated across independent cell cultures and across human and mouse OS. RESULTS: The results from the genetic and chemical screens significantly overlapped, with a profound enrichment of pathways regulated by PI3K and mTOR pathways. Drugs that concurrently target both PI3K and mTOR were effective at inducing apoptosis in primary OS cell cultures in vitro in both human and mouse OS, while specific PI3K or mTOR inhibitors were not effective. The results were confirmed with siRNA and small molecule approaches. Rationale combinations of specific PI3K and mTOR inhibitors could recapitulate the effect on OS cell cultures. CONCLUSIONS: The approaches described here have identified dual inhibition of the PI3K/mTOR pathway as a sensitive, druggable target in OS and provide rationale for translational studies with these agents.
AACR
Chemical Biology ; Cancer and Haematology ; Systems Biology and Personalised Medicine
10.1158/1078-0432.CCR-14-3026
25862761
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2015-05-20 10:11:20 Last Modified 2020-04-07 02:27:08