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KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer

Andrew M Waters1, Channing J Der1

  • 1University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599.

Cold Spring Harbor Perspectives in Medicine
|December 13, 2017
PubMed

Insights

RAS genes are frequently mutated in deadly cancers like lung, colorectal, and pancreatic cancer. Despite decades of research, effective RAS inhibitors remain elusive, but new strategies offer hope for targeting KRAS, especially in pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • RAS genes (HRAS, KRAS, NRAS) are the most frequently mutated oncogene family in human cancers.
  • RAS mutations are prevalent in lung, colorectal, and pancreatic cancers, the leading causes of cancer death in the US.
  • Despite extensive research, effective RAS inhibitors have not yet been developed, highlighting the challenge of targeting these 'undruggable' proteins.

Purpose of the Study:

  • To review the critical role of KRAS as a driver oncogene in pancreatic ductal adenocarcinoma (PDAC).
  • To discuss KRAS as a therapeutic target in PDAC, given its near 100% mutation frequency in this cancer.
  • To provide an overview of the challenges and renewed hope in developing anti-RAS therapies.

Main Methods:

  • Literature review focusing on RAS gene mutations in cancer.
  • Analysis of KRAS mutation frequency and its significance in various cancers, particularly PDAC.
  • Synthesis of information regarding past failures and emerging strategies for RAS-targeted therapy.

Main Results:

  • KRAS is the most frequently mutated RAS isoform, implicated in 84% of all RAS-mutant cancers.
  • Pancreatic ductal adenocarcinoma (PDAC) exhibits the highest RAS addiction, with near 100% KRAS mutation frequency.
  • The development of effective anti-RAS therapies remains a significant challenge despite ongoing efforts.

Conclusions:

  • KRAS is a pivotal driver and therapeutic target in pancreatic ductal adenocarcinoma.
  • Overcoming the 'undruggable' nature of RAS presents a major hurdle in cancer therapy development.
  • Renewed strategies and insights offer optimism for future anti-RAS drug discovery.

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