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

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: 25862761Gupte 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.