TY - JOUR
T1 - An integrin β 3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition
AU - Seguin, Laetitia
AU - Kato, Shumei
AU - Franovic, Aleksandra
AU - Camargo, M. Fernanda
AU - Lesperance, Jacqueline
AU - Elliott, Kathryn C.
AU - Yebra, Mayra
AU - Mielgo, Ainhoa
AU - Lowy, Andrew M.
AU - Husain, Hatim
AU - Cascone, Tina
AU - Diao, Lixia
AU - Wang, Jing
AU - Wistuba, Ignacio I.
AU - Heymach, John V.
AU - Lippman, Scott M.
AU - Desgrosellier, Jay S.
AU - Anand, Sudarshan
AU - Weis, Sara M.
AU - Cheresh, David A.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84899860489&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899860489&partnerID=8YFLogxK
U2 - 10.1038/ncb2953
DO - 10.1038/ncb2953
M3 - Article
C2 - 24747441
AN - SCOPUS:84899860489
SN - 1465-7392
VL - 16
SP - 457
EP - 468
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 5
ER -