An integrin β 3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition

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

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin v 2 3 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, v 2 3, 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, v 2 3 expression and the resulting KRAS-RalB-NF-κ B 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 v 2 3 as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.

Original languageEnglish (US)
Pages (from-to)457-468
Number of pages12
JournalNature Cell Biology
Volume16
Issue number5
DOIs
StatePublished - 2014
Externally publishedYes

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Integrins
Neoplasms
Cell Membrane
Neoplastic Stem Cells
Receptor Protein-Tyrosine Kinases
Drug Resistance
Heterografts
Lung Neoplasms
Pharmacology
Breast Neoplasms
Carcinoma
Lung
Erlotinib Hydrochloride
Therapeutics

ASJC Scopus subject areas

  • Cell Biology

Cite this

Seguin, L., Kato, S., Franovic, A., Camargo, M. F., Lesperance, J., Elliott, K. C., ... Cheresh, D. A. (2014). An integrin β 3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nature Cell Biology, 16(5), 457-468. https://doi.org/10.1038/ncb2953

An integrin β 3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. / 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.

In: Nature Cell Biology, Vol. 16, No. 5, 2014, p. 457-468.

Research output: Contribution to journalArticle

Seguin, L, Kato, S, Franovic, A, Camargo, MF, Lesperance, J, Elliott, KC, Yebra, M, Mielgo, A, Lowy, AM, Husain, H, Cascone, T, Diao, L, Wang, J, Wistuba, II, Heymach, JV, Lippman, SM, Desgrosellier, JS, Anand, S, Weis, SM & Cheresh, DA 2014, 'An integrin β 3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition', Nature Cell Biology, vol. 16, no. 5, pp. 457-468. https://doi.org/10.1038/ncb2953
Seguin L, Kato S, Franovic A, Camargo MF, Lesperance J, Elliott KC et al. An integrin β 3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nature Cell Biology. 2014;16(5):457-468. https://doi.org/10.1038/ncb2953
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. / An integrin β 3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. In: Nature Cell Biology. 2014 ; Vol. 16, No. 5. pp. 457-468.
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