American Association for Cancer Research
00085472can124502-sup-fig_2.pdf (163.46 kB)

Supplementary Figure 2 from Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling

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journal contribution
posted on 2023-03-30, 21:41 authored by Rina Kanda, Akihiko Kawahara, Kosuke Watari, Yuichi Murakami, Kahori Sonoda, Masashi Maeda, Hideaki Fujita, Masayoshi Kage, Hidetaka Uramoto, Carlota Costa, Michihiko Kuwano, Mayumi Ono

PDF - 163K, A, Establishment of stable integrinβ1-overexpressing cell lines (PC9/ITG2 and PC9/ITG11) or control cDNA transfected cell line (PC9/Mock) from PC9 cells by transfection with integrinβ1 cDNA. B, The effect of integrinβ1 overexpression on erlotinib sensitivity. Transfectants were treated with erlotinib for 3 days, and the IC50 values (μM) for erlotinib were 0.04 (PC9/Mock), 0.09 (PC9/ITG2), and 0.10 (PC9/ITG11). C, Western blots showing the expression and phosphorylation of EGFR, integrinβ1, Akt, and Erk1/2 following exposure to erlotinib for 5 hr.



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. Cancer Res; 73(20); 6243–53. ©2013 AACR.