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Author Spotlight: Investigating Angiogenesis and Vessel Permeability Through a Modified Matrix Gel Plug Assay
09:03

Author Spotlight: Investigating Angiogenesis and Vessel Permeability Through a Modified Matrix Gel Plug Assay

Published on: June 30, 2023

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KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas

Kayoko Hosaka1, Patrik Andersson1, Jieyu Wu1

  • 1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 171 65, Sweden.

Proceedings of the National Academy of Sciences of the United States of America
|July 10, 2023
PubMed

Insights

KRAS mutations in epithelial cancers cause resistance to anti-VEGF drugs by increasing angiopoietin 2 (ANG2). Combination therapy with anti-VEGF and anti-ANG2 drugs shows potent anticancer effects in these tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Antiangiogenic drugs (AADs) face challenges in predicting therapeutic benefits and overcoming drug resistance.
  • Currently, no reliable biomarkers exist to guide AAD treatment in cancer patients.

Purpose of the Study:

  • To investigate the mechanism of AAD resistance in epithelial carcinomas with KRAS mutations.
  • To identify potential therapeutic strategies for KRAS-mutated cancers resistant to AADs.

Main Methods:

  • Investigated the role of KRAS mutations in regulating angiopoietin 2 (ANG2) expression.
  • Examined the impact of ANG2 on tumor angiogenesis and resistance to anti-VEGF therapy.
  • Evaluated the efficacy of combination therapy with anti-VEGF and anti-ANG2 drugs in preclinical models.

Main Results:

  • KRAS mutations up-regulate FOXC2, leading to increased ANG2 expression and VEGF-independent tumor angiogenesis.
  • Cancers with KRAS mutations exhibit intrinsic resistance to monotherapies targeting VEGF or ANG2.
  • Combination therapy with anti-VEGF and anti-ANG2 drugs demonstrated synergistic anticancer effects in KRAS-mutated cancers.

Conclusions:

  • KRAS mutations serve as a predictive marker for resistance to anti-VEGF therapy.
  • Targeting both VEGF and ANG2 pathways offers a promising therapeutic strategy for KRAS-mutated epithelial carcinomas.
Keywords:
ANG2Ras mutationVEGFcancerdrug resistance

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