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An integrin β₃-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition

Laetitia Seguin1, Shumei Kato2, Aleksandra Franovic1

  • 1Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.

Nature Cell Biology
|April 22, 2014
PubMed

Insights

Integrin α(v)β₃ marks aggressive, drug-resistant cancer stem cells. Targeting the KRAS-RalB-NF-κB pathway with bortezomib reversed stemness and erlotinib resistance, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Tumour cells with stem-like properties are linked to cancer aggression and drug resistance.
  • Receptor tyrosine kinase (RTK) inhibitors like erlotinib are often ineffective against these aggressive tumour cells.

Purpose of the Study:

  • To identify markers and mechanisms driving stem-like properties and drug resistance in carcinomas.
  • To investigate the role of integrin α(v)β₃ in erlotinib resistance.
  • To explore therapeutic strategies targeting this pathway.

Main Methods:

  • In vitro and in vivo studies using patient-derived tumour xenografts.
  • Analysis of clinical specimens from lung cancer patients.
  • Investigating the recruitment of KRAS and RalB to the plasma membrane by α(v)β₃.
  • Assessing the activation of TBK1 and NF-κB.
  • Evaluating the efficacy of bortezomib in reversing tumour stemness and drug resistance.

Main Results:

  • Integrin α(v)β₃ was identified as a marker for breast, lung, and pancreatic carcinomas with stem-like properties resistant to erlotinib.
  • α(v)β₃ recruits KRAS and RalB, activating the TBK1-NF-κB pathway, which drives tumour initiation, self-renewal, and erlotinib resistance.
  • Pharmacological inhibition of this pathway with bortezomib effectively reversed tumour stemness and erlotinib resistance.

Conclusions:

  • Integrin α(v)β₃ is a crucial marker and driver of carcinoma stemness and resistance to RTK inhibitors.
  • The KRAS-RalB-NF-κB pathway activated by α(v)β₃ is essential for tumour initiation and maintenance.
  • Targeting the α(v)β₃-mediated pathway presents a promising therapeutic strategy to sensitize resistant tumours to RTK inhibitors.

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