2. Academic Validation
  3. MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival

MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival

  • Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4508-4517. doi: 10.1073/pnas.1817494116.
Chih-Shia Lee 1,  Liam C Lee 1,  Tina L Yuan 2,  Sirisha Chakka 3,  Christof Fellmann 4,  Scott W Lowe 4 5 6,  Natasha J Caplen 3,  Frank McCormick 7 8,  Ji Luo 9
Affiliations

Affiliations

  • 1 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
  • 2 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
  • 3 Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
  • 4 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • 5 Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 6 Department of Cancer Biology & Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 7 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158; frank.mccormick@ucsf.edu ji.luo@nih.gov.
  • 8 Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21702.
  • 9 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892; frank.mccormick@ucsf.edu ji.luo@nih.gov.
PMID: 30709910 DOI: 10.1073/pnas.1817494116
Abstract

Oncogenic mutations in the small GTPase KRAS are frequently found in human cancers, and, currently, there are no effective targeted therapies for these tumors. Using a combinatorial siRNA approach, we analyzed a panel of KRAS mutant colorectal and pancreatic Cancer cell lines for their dependency on 28 gene nodes that represent canonical Ras effector pathways and selected stress response pathways. We found that Raf node knockdown best differentiated KRAS mutant and KRAS WT Cancer cells, suggesting Raf kinases are key oncoeffectors for KRAS addiction. By analyzing all 376 pairwise combination of these gene nodes, we found that cotargeting the Raf, RAC, and Autophagy pathways can improve the capture of KRAS dependency better than targeting Raf alone. In particular, codepletion of the oncoeffector kinases BRaf and CRAF, together with the Autophagy E1 Ligase ATG7, gives the best therapeutic window between KRAS mutant cells and normal, untransformed cells. Distinct patterns of Ras effector dependency were observed across KRAS mutant cell lines, indicative of heterogeneous utilization of effector and stress response pathways in supporting KRAS addiction. Our findings revealed previously unappreciated complexity in the signaling network downstream of the KRAS oncogene and suggest rational target combinations for more effective therapeutic intervention.

Keywords

KRAS; MAPK; RAF; autophagy; siRNA.

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