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Survival of pancreatic cancer cells lacking KRAS function

Mandar Deepak Muzumdar1,2,3, Pan-Yu Chen1,4, Kimberly Judith Dorans1

  • 1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Nature Communications
|October 25, 2017
PubMed

Insights

KRAS is not essential in all pancreatic cancer cells, with some showing PI3K-dependent signaling and sensitivity to PI3K inhibitors. KRAS also suppresses metastasis, impacting treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Activating KRAS mutations are common in pancreatic ductal adenocarcinoma (PDAC).
  • Effective therapeutic options for PDAC remain limited, despite ongoing efforts to develop KRAS-targeted drugs.
  • The complete dependence of PDAC cells on KRAS is not fully understood.

Purpose of the Study:

  • To investigate the dispensability of KRAS in PDAC cells.
  • To explore alternative signaling pathways and therapeutic vulnerabilities in KRAS-independent PDAC.
  • To understand KRAS's role in suppressing metastasis in PDAC.

Main Methods:

  • CRISPR/Cas-mediated genome editing to model complete KRAS inhibition.
  • Analysis of phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling.
  • Gene expression profiling of KRAS-dependent and KRAS-independent PDAC cells.

Main Results:

  • KRAS was found to be dispensable in a subset of human and mouse PDAC cells.
  • KRAS-deficient cells displayed PI3K-dependent MAPK signaling and sensitivity to PI3K inhibitors.
  • KRAS was identified to suppress metastasis-related genes in PDAC cells.

Conclusions:

  • PDAC cells can be resistant to KRAS inhibitors.
  • PI3K inhibitors represent a potential therapeutic strategy for KRAS-independent PDAC.
  • KRAS plays a role in regulating metastasis in pancreatic cancer.

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