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

Rina Kanda, Akihiko Kawahara, Kosuke Watari, Yuichi Murakami, Kahori Sonoda, Masashi Maeda, Hideaki Fujita, Masayoshi Kage, Hidetaka Uramoto, Carlota Costa, Michihiko Kuwano, Mayumi Ono

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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, a2, and a5 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.

Original languageEnglish
Pages (from-to)6243-6253
Number of pages11
JournalCancer Research
Volume73
Issue number20
DOIs
Publication statusPublished - Oct 15 2013

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Integrins
Lung Neoplasms
Epidermal Growth Factor Receptor
Mutation
RNA Interference
Drug Resistance
Cell Adhesion
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Erlotinib Hydrochloride
Phosphotransferases
Therapeutics
Phosphorylation
Growth
Pharmaceutical Preparations
Neoplasms
gefitinib

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. / Kanda, Rina; Kawahara, Akihiko; Watari, Kosuke; Murakami, Yuichi; Sonoda, Kahori; Maeda, Masashi; Fujita, Hideaki; Kage, Masayoshi; Uramoto, Hidetaka; Costa, Carlota; Kuwano, Michihiko; Ono, Mayumi.

In: Cancer Research, Vol. 73, No. 20, 15.10.2013, p. 6243-6253.

Research output: Contribution to journalArticle

Kanda, R, Kawahara, A, Watari, K, Murakami, Y, Sonoda, K, Maeda, M, Fujita, H, Kage, M, Uramoto, H, Costa, C, Kuwano, M & Ono, M 2013, 'Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling', Cancer Research, vol. 73, no. 20, pp. 6243-6253. https://doi.org/10.1158/0008-5472.CAN-12-4502
Kanda, Rina ; Kawahara, Akihiko ; Watari, Kosuke ; Murakami, Yuichi ; Sonoda, Kahori ; Maeda, Masashi ; Fujita, Hideaki ; Kage, Masayoshi ; Uramoto, Hidetaka ; Costa, Carlota ; Kuwano, Michihiko ; Ono, Mayumi. / Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. In: Cancer Research. 2013 ; Vol. 73, No. 20. pp. 6243-6253.
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