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

  1. Author:
    Lee, Chih-Shia
    Lee, Liam C.
    Yuan, Tina L.
    Chakka, Sirisha
    Fellmann, Christof
    Lowe, Scott W.
    Caplen, Natasha J.
    McCormick, Frank
    Luo, Ji

  2. Author Address

    NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA.Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA.Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA.Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA.Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA.Leidos Biomed Res, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD 21702 USA.Loxo Oncol, Med Affairs, Stamford, CT 06901 USA.Novartis Inst Biomed Res, Oncol Translat Res, Cambridge, MA 02139 USA.NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA.Gladstone Inst, Inst Data Sci & Biotechnol, San Francisco, CA 94158 USA.
    1. Year: 2019
    2. Date: Mar 5
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
  3. NATL ACAD SCIENCES,
    1. 116
    2. 10
    3. Pages: 4508-4517
  5. Type of Article: Article
  6. ISSN: 0027-8424
  1. 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.

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External Sources

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  2. DOI: 10.1073/pnas.1817494116
  3. PMID: 30709910
  4. PMCID: PMC6410784
  5. View record in Web of Science®
  6. WOS: 000460242100085

Library Notes

  1. Fiscal Year: FY2018-2019
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