Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells.
Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells.
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DOI：
10.1002/mc.22342
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发表时间：
2016-05
影响因子：
4.6
通讯作者：
You M
中科院分区：
文献类型：
--
作者：
Lee Y;Wang Y;James M;Jeong JH;You M
表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者已从可逆性EGFR酪氨酸激酶抑制剂（TKI）（如吉非替尼和厄洛替尼）治疗中获益。EGFR T790 M中获得继发性突变是第一代EGFR TKI耐药的最常见机制，导致治疗失败。阿法替尼是第二代EGFR TKI，对携带EGFR T790 M突变的肿瘤显示出很好的疗效，但可能由于新的获得性耐药机制，阿法替尼未能改善携带EGFR突变的肺癌患者的总生存期。目前，对阿法替尼产生获得性耐药的肺癌患者尚无治疗选择。为了确定阿法替尼的新耐药机制，我们从携带EGFR L 858 R和T790 M突变的亲本人源NSCLC细胞系H1975中开发了阿法替尼耐药细胞系。我们发现，胰岛素样生长因子1受体（IGF 1 R）信号通路的激活有助于携带T790 M突变的NSCLC细胞对阿法替尼耐药。IGF 1 R敲低不仅使耐药细胞对阿法替尼显著敏感，而且诱导阿法替尼耐药细胞凋亡。此外，阿法替尼和林西替尼联合治疗对体内H1975异种移植物中肿瘤生长的影响超过累加效应。因此，这些发现表明，IGF 1 R抑制或EGFR-IGF 1 R抑制策略的组合将是预防或增强对第一代或第二代EGFR TKI耐药的肺癌患者当前治疗选择的作用的潜在方法
Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation have benefited from treatment of reversible EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Acquisition of a secondary mutation in EGFR T790M is the most common mechanism of resistance to first generation EGFR TKIs, resulting in therapeutic failure. Afatinib is a second generation of EGFR TKI that showed great efficacy against tumors bearing the EGFR T790M mutation, but it failed to show the improvement on overall survival of lung cancer patients with EGFR mutations possibly because of novel acquired resistance mechanisms. Currently, there are no therapeutic options available for lung cancer patients who develop acquired resistance to afatinib. To identify novel resistance mechanism(s) to afatinib, we developed afatinib resistant cell lines from a parental human-derived NSCLC cell line, H1975, harboring both EGFR L858R and T790M mutations. We found that activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway contributes to afatinib resistance in NSCLC cells harboring the T790M mutation. IGF1R knockdown not only significantly sensitizes resistant cells to afatinib, but also induces apoptosis in afatinib resistance cells. In addition, combination treatment with afatinib and linsitinib shows more than additive effects on tumor growth in in vivo H1975 xenograft. Therefore, these finding suggest that IGF1R inhibition or combination of EGFR-IGF1R inhibition strategies would be potential ways to prevent or potentiate the effects of current therapeutic options to lung cancer patients demonstrating resistance to either first or second generation EGFR TKIs
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