Differential Effector Engagement by Oncogenic KRAS
oleh: 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
| Format: | Article |
|---|---|
| Diterbitkan: | Elsevier 2018-02-01 |
Deskripsi
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.