Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies

Sajid Khan, Vivekananda Budamagunta, Daohong Zhou

Research output: Chapter in Book/Report/Conference proceedingChapter

6 Scopus citations

Abstract

KRAS, a predominant member of the RAS family, is the most frequently mutated oncogene in human pancreatic cancer (∼95% of cases). Mutations in KRAS lead to its constitutive activation and activation of its downstream signaling pathways such as RAF/MEK/ERK and PI3K/AKT/mTOR that promote cell proliferation and provide apoptosis evasion capabilities to cancer cells. KRAS had been considered ‘undruggable’ until the discovery of the first covalent inhibitor targeting the G12C mutation. While G12C mutations are frequently found in non-small cell lung cancer, these are relatively rare in pancreatic cancer. On the other hand, pancreatic cancer harbors other KRAS mutations such as G12D and G12V. The inhibitors targeting G12D mutation (such as MRTX1133) have been recently developed, whereas those targeting other mutations are still lacking. Unfortunately, KRAS inhibitor monotherapy-associated resistance hinders their therapeutic efficacy. Therefore, various combination strategies have been tested and some yielded promising results, such as combinations with receptor tyrosine kinase, SHP2, or SOS1 inhibitors. In addition, we recently demonstrated that the combination of sotorasib with DT2216 (a BCL-XL-selective degrader) synergistically inhibits G12C-mutated pancreatic cancer cell growth in vitro and in vivo. This is in part because KRAS-targeted therapies induce cell cycle arrest and cellular senescence, which contributes to therapeutic resistance, while their combination with DT2216 can more effectively induce apoptosis. Similar combination strategies may also work for G12D inhibitors in pancreatic cancer. This chapter will review KRAS biochemistry, signaling pathways, different mutations, emerging KRAS-targeted therapies, and combination strategies. Finally, we discuss challenges associated with KRAS targeting and future directions, emphasizing pancreatic cancer.

Original languageEnglish (US)
Title of host publicationPancreatic Cancer
Subtitle of host publicationBasic Mechanisms and Therapies
EditorsLuni Emdad, Azeddine Atfi, Rajan Gogna, Jose G. Trevino, Paul B. Fisher
PublisherAcademic Press Inc.
Pages145-184
Number of pages40
ISBN (Print)9780443133541
DOIs
StatePublished - Jan 2023
Externally publishedYes

Publication series

NameAdvances in Cancer Research
Volume159
ISSN (Print)0065-230X
ISSN (Electronic)2162-5557

Keywords

  • Combinatorial therapy
  • Drug resistance
  • KRAS
  • Oncogenic signaling
  • Pancreatic cancer
  • Senescence
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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