Abstract

A comprehensive understanding of the molecular vulnerabilities of every type of cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project will identify genes with aberrant copy number, sequence, or expression in various cancer types, providing a survey of the genes that may have a causal role in cancer. A complementary approach is to perform systematic loss-of-function studies to identify essential genes in particular cancer cell types. We have begun a systematic effort, termed Project Achilles, aimed at identifying genetic vulnerabilities across large numbers of cancer cell lines. Here, we report the assessment of the essentiality of 11,194 genes in 102 human cancer cell lines. We show that the integration of these functional data with information derived from surveying cancer genomes pinpoints known and previously undescribed lineage-specific dependencies across a wide spectrum of cancers. In particular, we found 54 genes that are specifically essential for the proliferation and viability of ovarian cancer cells and also amplified in primary tumors or differentially overexpressed in ovarian cancer cell lines. One such gene, PAX8, is focally amplified in 16% of high-grade serous ovarian cancers and expressed at higher levels in ovarian tumors. Suppression of PAX8 selectively induces apoptotic cell death of ovarian cancer cells. These results identify PAX8 as an ovarian lineage-specific dependency. More generally, these observations demonstrate that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways.

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Acknowledgments

We thank M. Reich, A. Derr, and T. Liefield for assistance with analysis and data portal creation. This work was supported in part by National Institutes of Health Grants R33 CA128625, U54 CA112962, and RC2 CA148268, Novartis Pharmaceuticals, Richard Hunt, and the H. L. Snyder Foundation.

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 108 | No. 30
July 26, 2011
PubMed: 21746896

Classifications

Submission history

Published online: July 11, 2011
Published in issue: July 26, 2011

Keywords

  1. high throughput
  2. RNAi
  3. oncogene
  4. lineage

Acknowledgments

We thank M. Reich, A. Derr, and T. Liefield for assistance with analysis and data portal creation. This work was supported in part by National Institutes of Health Grants R33 CA128625, U54 CA112962, and RC2 CA148268, Novartis Pharmaceuticals, Richard Hunt, and the H. L. Snyder Foundation.

Authors

Affiliations

Hiu Wing Cheung1
Department of Medical Oncology,
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Glenn S. Cowley1
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Barbara A. Weir1
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Jesse S. Boehm1
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Scott Rusin
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Justine A. Scott
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Alexandra East
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Levi D. Ali
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Patrick H. Lizotte
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Terence C. Wong
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Guozhi Jiang
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Jessica Hsiao
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Craig H. Mermel
Department of Medical Oncology,
Center for Cancer Genome Discovery and
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Gad Getz
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Jordi Barretina
Department of Medical Oncology,
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Shuba Gopal
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Pablo Tamayo
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Joshua Gould
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Aviad Tsherniak
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Nicolas Stransky
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Biao Luo
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Yin Ren
Harvard-MIT Division of Health Sciences and Technology and
Ronny Drapkin
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115;
Departments of ePathology and
Sangeeta N. Bhatia
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Harvard-MIT Division of Health Sciences and Technology and
Electrical Engineering and Computer Science, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and
Howard Hughes Medical Institute, Chevy Chase, MD 20815
Jill P. Mesirov
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Levi A. Garraway
Department of Medical Oncology,
Center for Cancer Genome Discovery and
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and
Matthew Meyerson
Department of Medical Oncology,
Center for Cancer Genome Discovery and
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Departments of ePathology and
Eric S. Lander2 [email protected]
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
David E. Root2 [email protected]
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
William C. Hahn2 [email protected]
Department of Medical Oncology,
Center for Cancer Genome Discovery and
Broad Institute of Harvard and MIT, Cambridge, MA 02142;
Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and

Notes

2
To whom correspondence may be addressed. E-mail: [email protected], [email protected], or [email protected].
Author contributions: H.W.C., G.S.C., B.A.W., J.S.B., E.S.L., D.E.R., and W.C.H. designed research; H.W.C., G.S.C., B.A.W., J.S.B., S.R., J.A.S., A.E., L.D.A., P.H.L., T.C.W., G.J., and J.H. performed research; C.H.M., G.G., J.B., S.G., P.T., A.T., N.S., B.L., Y.R., R.D., S.N.B., and L.A.G. contributed new reagents/analytic tools; B.A.W., S.G., P.T., J.G., A.T., J.P.M., M.M., E.S.L., D.E.R., and W.C.H. analyzed data; and H.W.C., G.S.C., B.A.W., J.S.B., E.S.L., D.E.R., and W.C.H. wrote the paper.
1
H.W.C., G.S.C., B.A.W., and J.S.B. contributed equally to this work.

Competing Interests

Conflict of interest statement: R.D., L.A.G., M.M., and W.C.H. are consultants for Novartis Pharmaceuticals.

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    Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer
    Proceedings of the National Academy of Sciences
    • Vol. 108
    • No. 30
    • pp. 12187-12559

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