title: Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling.
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.
authors.affiliation: 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.
authors.forename: Rina
authors.initials: R
authors.lastname: Kanda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kawahara
authors.forename: Kosuke
authors.initials: K
authors.lastname: Watari
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Murakami
authors.forename: Kahori
authors.initials: K
authors.lastname: Sonoda
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujita
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kage
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.forename: Carlota
authors.initials: C
authors.lastname: Costa
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D055785:Gene Knockdown Techniques; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019061:src-Family Kinases; D051058:Oncogene Protein v-akt