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

Clin Cancer Res. 2015 Jul 15;21(14):3216-29. doi: 10.1158/1078-0432.CCR-14-3026. Epub 2015 Apr 10.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / genetics*
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Drug Screening Assays, Antitumor / methods
  • Genetic Engineering
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mice
  • Osteosarcoma / genetics*
  • Phosphoinositide-3 Kinase Inhibitors*
  • RNA, Small Interfering
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Small Interfering
  • TOR Serine-Threonine Kinases