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.
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.