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Survival of pancreatic cancer cells lacking KRAS function

Author

Listed:
  • Mandar Deepak Muzumdar

    (Massachusetts Institute of Technology
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Pan-Yu Chen

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Kimberly Judith Dorans

    (Massachusetts Institute of Technology)

  • Katherine Minjee Chung

    (Massachusetts Institute of Technology)

  • Arjun Bhutkar

    (Massachusetts Institute of Technology)

  • Erin Hong

    (Massachusetts Institute of Technology)

  • Elisa M. Noll

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
    German Cancer Research Center (DKFZ))

  • Martin R. Sprick

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
    German Cancer Research Center (DKFZ))

  • Andreas Trumpp

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM)
    German Cancer Research Center (DKFZ))

  • Tyler Jacks

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

Abstract

Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition.

Suggested Citation

  • Mandar Deepak Muzumdar & Pan-Yu Chen & Kimberly Judith Dorans & Katherine Minjee Chung & Arjun Bhutkar & Erin Hong & Elisa M. Noll & Martin R. Sprick & Andreas Trumpp & Tyler Jacks, 2017. "Survival of pancreatic cancer cells lacking KRAS function," Nature Communications, Nature, vol. 8(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00942-5
    DOI: 10.1038/s41467-017-00942-5
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    Cited by:

    1. Ming Yi & Ruoqing Zhu & Robert M Stephens, 2018. "GradientScanSurv—An exhaustive association test method for gene expression data with censored survival outcome," PLOS ONE, Public Library of Science, vol. 13(12), pages 1-28, December.
    2. Boyang Zhao & Yiyun Rao & Scott Leighow & Edward P. O’Brien & Luke Gilbert & Justin R. Pritchard, 2022. "A pan-CRISPR analysis of mammalian cell specificity identifies ultra-compact sgRNA subsets for genome-scale experiments," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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