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Updated: Oct 18, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

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Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer

Shinkyo Yoon1, Hannah Yang2, Hyun-Min Ryu1,3

  • 1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Cancer Research and Treatment
|October 4, 2021
PubMed
Abstract

Insights

Heat shock protein-90 (HSP90) inhibitors like AUY922 show modest efficacy in KRAS-mutant NSCLC. Resistance involves integrin signaling, but targeting FAK and HSP90 may overcome this for better cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Heat shock protein-90 (HSP90) is a key target in cancer due to its role in oncogenic pathways.
  • HSP90 inhibitors, including AUY922, have shown limited success in KRAS-mutant non-small cell lung cancer (NSCLC) due to resistance and toxicity.

Purpose of the Study:

  • To investigate the novel mechanisms of AUY922 resistance in KRAS-mutant NSCLC.
  • To identify potential strategies for overcoming resistance and developing next-generation HSP90 inhibitors.

Main Methods:

  • Established AUY922-resistant KRAS-mutant NSCLC cell lines.
  • Utilized RNA sequencing to identify resistance biomarkers.
  • Validated findings in vitro and in vivo xenograft models.

Main Results:

  • Identified integrin αv (ITGAv) and β3 (ITGB3) as novel resistance biomarkers.
  • ITGAv and ITGB3 promote AUY922 resistance via focal adhesion kinase (FAK) activation and epithelial-mesenchymal transition.
  • Downregulation of miR-142 and miR-150 led to increased ITGAv and ITGB3, respectively.
  • Overexpression of miR-150 and miR-142 restored AUY922 sensitivity by inhibiting ITGAvβ3-dependent FAK activation.

Conclusions:

  • Synergistic co-targeting of FAK and HSP90 attenuated the growth of AUY922-resistant KRAS-mutant NSCLC cells.
  • This combination strategy holds promise for overcoming acquired AUY922 resistance in KRAS-mutant NSCLC.
Keywords:
Combination therapyHSP90 inhibitorIntegrinKRAS mutationNSCLC

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