Cell Reports (Feb 2018)
Differential Effector Engagement by Oncogenic KRAS
- Tina L. Yuan,
- Arnaud Amzallag,
- Rachel Bagni,
- Ming Yi,
- Shervin Afghani,
- William Burgan,
- Nicole Fer,
- Leslie A. Strathern,
- Katie Powell,
- Brian Smith,
- Andrew M. Waters,
- David Drubin,
- Ty Thomson,
- Rosy Liao,
- Patricia Greninger,
- Giovanna T. Stein,
- Ellen Murchie,
- Eliane Cortez,
- Regina K. Egan,
- Lauren Procter,
- Matthew Bess,
- Kwong Tai Cheng,
- Chih-Shia Lee,
- Liam Changwoo Lee,
- Christof Fellmann,
- Robert Stephens,
- Ji Luo,
- Scott W. Lowe,
- Cyril H. Benes,
- Frank McCormick
Affiliations
- Tina L. Yuan
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA
- Arnaud Amzallag
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Rachel Bagni
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Ming Yi
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Shervin Afghani
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA
- William Burgan
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Nicole Fer
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Leslie A. Strathern
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Katie Powell
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Brian Smith
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Andrew M. Waters
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- David Drubin
- Selventa, One Alewife Center, Suite 330, Cambridge, MA 02140, USA
- Ty Thomson
- Selventa, One Alewife Center, Suite 330, Cambridge, MA 02140, USA
- Rosy Liao
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Patricia Greninger
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Giovanna T. Stein
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Ellen Murchie
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Eliane Cortez
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Regina K. Egan
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
- Lauren Procter
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Matthew Bess
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Kwong Tai Cheng
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Chih-Shia Lee
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
- Liam Changwoo Lee
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
- Christof Fellmann
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Robert Stephens
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA
- Ji Luo
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
- Scott W. Lowe
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Cancer Biology & Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA
- Cyril H. Benes
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Corresponding author
- Frank McCormick
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA; Corresponding author
- DOI
- https://doi.org/10.1016/j.celrep.2018.01.051
- Journal volume & issue
-
Vol. 22,
no. 7
pp. 1889 – 1902
Abstract
Summary: KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3′ kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention.
Keywords
