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Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. | LitMetric

Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling.

Cancer Res

Authors' Affiliations: Department of Pharmaceutical Oncology and Laboratory of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka; Department of Diagnostic Pathology, Kurume University Hospital, Kurume; Section of Functional Morphology, Faculty of Pharmaceutical Science, Nagasaki International University, Nagasaki; Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu; St. Mary's Institute of Health Science, St. Mary's Hospital, Kurume, Japan; and Pangaea Biotech, Dexeus University Institute, Barcelona, Spain.

Published: October 2013

AI Article Synopsis

Article Abstract

EGF receptor (EGFR) kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non-small cell lung cancers harboring EGFR-activating mutations. However, most patients ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors and the reversal of which could improve clinical outcomes. In erlotinib-resistant lung cancer cells harboring activating EGFR mutations that we established, there was increased expression of Src, integrin β1, α2, and α5 along with enhanced cell adhesion activity. Interestingly, RNAi-mediated silencing of integrin β1 restored erlotinib sensitivity and reduced activation of Src and Akt after erlotinib treatment. Furthermore, Src silencing inhibited Akt phosphorylation and cell growth, with this inhibitory effect further augmented by erlotinib treatment. Increased expression of integrin β1, α5, and/or α2 was also observed in refractory tumor samples from patients with lung cancer treated with erlotinib and/or gefitinib. Together, our findings identify the integrin β1/Src/Akt signaling pathway as a key mediator of acquired resistance to EGFR-targeted anticancer drugs.

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Source
http://dx.doi.org/10.1158/0008-5472.CAN-12-4502DOI Listing

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