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Systematic Screening Identifies Dual PI3K and mTOR Inhibition as a Conserved Therapeutic Vulnerability in Osteosarcoma.

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Version 2 2015-07-09, 07:16
Version 1 2015-07-09, 06:56
posted on 2015-07-09, 06:56 authored by ALISTAIR CHALK, CARL WALKLEYCARL WALKLEY, EMMA BAKER, Ankita Gupte, SOO-SAN WANSOO-SAN WAN, Elizabeth Stewart, Amos Loh, Anang A. Shelat, Cathryn M. Gould, Scott Taylor, Kurt Lackovic, Anthony J. Mutsaers, JAYESH DESAI, Piyush B. Madhamshettiwa, Andrew C.W. Zannettino, Chris Burns, DAVID HUANGDAVID HUANG, Michael A. Dyer, Kaylene J. Simpson

Systematic Screening Identifies Dual PI3K and mTOR Inhibition as a Conserved Therapeutic Vulnerability in Osteosarcoma.

PURPOSE: Osteosarcoma is the most common cancer of bone occurring mostly in
      teenagers. Despite rapid advances in our knowledge of the genetics and cell
      biology of osteosarcoma, 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 osteosarcoma patients.
      EXPERIMENTAL DESIGN: We have used genetically engineered murine models of human
      osteosarcoma 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 osteosarcoma-derived cell
      cultures. All results were validated across independent cell cultures and across 
      human and mouse osteosarcoma. 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 osteosarcoma cell cultures
      in vitro in both human and mouse osteosarcoma, whereas 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 osteosarcoma cell cultures. CONCLUSIONS: The
      approaches described here have identified dual inhibition of the PI3K-mTOR
      pathway as a sensitive, druggable target in osteosarcoma, and provide rationale
      for translational studies with these agents. Clin Cancer Res; 1-14. (c)2015 AACR.

Gupte A, Baker EK, Wan SS, Stewart E, Loh A, Shelat AA, Gould CM, Chalk AM, Taylor S, Lackovic K, Karlström Å, Mutsaers AJ, Desai J, Madhamshettiwar PB, Zannettino AC, Burns C, Huang DC, Dyer MA, Simpson KJ, Walkley CR.

Clin Cancer Res. 2015 Apr 10.

PMID: 25862761

Gupte et al Supp_dataset_1_siRNA_mouse_OS494_All-Data.xlsx : Raw and processed shRNA screen data.

Gupte et al Supp_dataset_2_KinaselibraryWEHI_mouseOS.xlsx : Data from chemical screen.


This work was supported by grants from the AACR-Aflac Inc, Career Development Award for Pediatric Cancer Research (to C.R. Walkley; 12-20-10- WALK); Colin North (to C.R. Walkley); Zig Inge Foundation (to C.R. Walkley); 5-point foundation (to E.K. Baker);