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.
Cancer Res. 2013 Oct 15;73(20):6243-53. doi: 10.1158/0008-5472.CAN-12-4502. Epub 2013 Jul 19.
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.
表皮生长因子受体（EGFR）激酶抑制剂，包括吉非替尼和厄洛替尼，在携带有 EGFR 激活突变的非小细胞肺癌中发挥了强大的治疗效果。然而，大多数患者最终会对这些药物产生耐药性。在这里，我们报告了一种针对 EGFR 酪氨酸激酶抑制剂获得性耐药的新机制，逆转这种机制可以改善临床结果。在我们建立的携带有激活 EGFR 突变的厄洛替尼耐药肺癌细胞中，Src、整合素β1、α2 和 α5 的表达增加，细胞黏附活性增强。有趣的是，RNAi 介导的整合素β1 沉默恢复了厄洛替尼的敏感性，并减少了厄洛替尼治疗后 Src 和 Akt 的激活。此外，Src 沉默抑制了 Akt 磷酸化和细胞生长，而厄洛替尼治疗进一步增强了这种抑制作用。在接受厄洛替尼和/或吉非替尼治疗的肺癌患者的耐药性肿瘤样本中，也观察到了整合素β1、α5 和/或α2 的表达增加。总之，我们的研究结果确定了整合素β1/Src/Akt 信号通路是 EGFR 靶向抗癌药物获得性耐药的关键介质。
