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

  • Author(s): Seguin, Laetitia
  • Kato, Shumei
  • Franovic, Aleksandra
  • Camargo, M Fernanda
  • Lesperance, Jacqueline
  • Elliott, Kathryn C
  • Yebra, Mayra
  • Mielgo, Ainhoa
  • Lowy, Andrew M
  • Husain, Hatim
  • Cascone, Tina
  • Diao, Lixia
  • Wang, Jing
  • Wistuba, Ignacio I
  • Heymach, John V
  • Lippman, Scott M
  • Desgrosellier, Jay S
  • Anand, Sudarshan
  • Weis, Sara M
  • Cheresh, David A
  • et al.

Published Web Location

http://10.0.4.14/ncb2953
No data is associated with this publication.
Abstract

Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)β₃ serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib. Mechanistically, α(v)β₃, in the unliganded state, recruits KRAS and RalB to the tumour cell plasma membrane, leading to the activation of TBK1 and NF-κB. In fact, α(v)β₃ expression and the resulting KRAS-RalB-NF-κB pathway were both necessary and sufficient for tumour initiation, anchorage independence, self-renewal and erlotinib resistance. Pharmacological targeting of this pathway with bortezomib reversed both tumour stemness and erlotinib resistance. These findings not only identify α(v)β₃ as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.

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