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

doi:10.1016/j.celrep.2018.01.051

Differential Effector Engagement by Oncogenic KRAS

Cell Rep. 2018 Feb 13;22(7):1889-1902. doi: 10.1016/j.celrep.2018.01.051.

Authors

Tina L Yuan¹, Arnaud Amzallag², Rachel Bagni³, Ming Yi³, Shervin Afghani¹, William Burgan³, Nicole Fer³, Leslie A Strathern³, Katie Powell³, Brian Smith³, Andrew M Waters³, David Drubin⁴, Ty Thomson⁴, Rosy Liao⁵, Patricia Greninger², Giovanna T Stein², Ellen Murchie², Eliane Cortez², Regina K Egan², Lauren Procter³, Matthew Bess³, Kwong Tai Cheng³, Chih-Shia Lee⁶, Liam Changwoo Lee⁶, Christof Fellmann⁷, Robert Stephens³, Ji Luo⁶, Scott W Lowe⁸, Cyril H Benes⁹, Frank McCormick¹⁰

Affiliations

¹ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA.
² Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
³ Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick, MD 21702, USA.
⁴ Selventa, One Alewife Center, Suite 330, Cambridge, MA 02140, USA.
⁵ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
⁷ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁸ 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.
⁹ Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: cbenes@mgh.harvard.edu.
¹⁰ 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. Electronic address: frank.mccormick@ucsf.edu.

Abstract

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: KRAS; RNAi screen; RSK; paralogs; redundancy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinase Kinases
Adenylate Kinase / metabolism
Cell Line, Tumor
Drug Evaluation, Preclinical
Gene Expression Regulation, Neoplastic / drug effects
Humans
Metabolic Networks and Pathways / drug effects
Models, Biological
Mutation / genetics
Oncogenes*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism*
RNA Interference
RNA, Small Interfering / metabolism
Small Molecule Libraries / pharmacology

Substances

KRAS protein, human
RNA, Small Interfering
Small Molecule Libraries
Protein Serine-Threonine Kinases
STK11 protein, human
AMP-Activated Protein Kinase Kinases
Adenylate Kinase
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding