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Oncogenic KRAS signaling and YAP1/β-catenin: Similar cell cycle control in tumor initiation

Ruth Nussinov1, Chung-Jung Tsai2, Hyunbum Jang2

  • 1Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

Seminars in Cell & Developmental Biology
|April 9, 2016
PubMed

Insights

Two independent cancer proliferation pathways, MAPK/ERK and PI3K/Akt/mTOR, and YAP1/c-Myc, can substitute or amplify each other. This finding offers new insights into KRAS-driven cancers and drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • KRAS-driven cancers frequently exhibit overexpression of YAP1 and c-Myc, contributing to drug resistance.
  • Understanding the interplay of signaling pathways is crucial for effective cancer therapy.

Purpose of the Study:

  • To investigate the independent and cooperative roles of two distinct signaling pathways in tumor proliferation.
  • To elucidate the mechanisms underlying YAP1 and c-Myc activation in KRAS-driven cancers and drug resistance.

Main Methods:

  • The study proposes a conceptual framework based on existing literature and proposes new hypotheses.
  • Analysis of signaling pathway interactions and their roles in cell cycle control and proliferation.

Main Results:

  • Two independent pathways driving tumor proliferation are identified: MAPK/ERK and PI3K/Akt/mTOR; and YAP1 and c-Myc.
  • These pathways can substitute for each other or amplify proliferation, explaining resistance to therapies targeting individual pathways.
  • The study highlights functional similarities between YAP1 and ERK, and between β-catenin and PI3K in cell cycle regulation.

Conclusions:

  • YAP1 and c-Myc activation represents an independent proliferation pathway in KRAS-driven cancers, offering alternative routes when other pathways are inhibited.
  • The proposed model provides a unified view of signaling-driven oncogenesis and suggests potential for pathway-based drug discovery targeting these independent or cooperative mechanisms.
Keywords:
CancerCellular pathwaysDrug resistanceHippoK-RasMycProliferationWNT

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