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Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Perry, J. A., Kiezun, A., Tonzi, P., Van Allen, E. M., Carter, S. L., Baca, S. C., Cowley, G. S., Bhatt, A. S., Rheinbay, E., Pedamallu, C. S., Helman, E., Taylor-Weiner, A., McKenna, A., DeLuca, D. S., Lawrence, M. S., Ambrogio, L., Sougnez, C., Sivachenko, A., Walensky, L. D., Wagle, N., Mora, J., de Torres, C., Lavarino, C., Aguiar, S. d., Yunes, J. A., Brandalise, S. R., Mercado-Celis, G. E., Melendez-Zajgla, J., Cardenas-Cardos, R., Velasco-Hidalgo, L., Roberts, C. W., Garraway, L. A., Rodriguez-Galindo, C., Gabriel, S. B., Lander, E. S., Golub, T. R., Orkin, S. H., Getz, G., Janeway, K. A. 2014; 111 (51): E5564-E5573

Abstract

Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo.

View details for DOI 10.1073/pnas.1419260111

View details for Web of Science ID 000346767200013

View details for PubMedID 25512523

View details for PubMedCentralID PMC4280630