T790M mutation–selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non–small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation–positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M-positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with downregulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFR-TKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M. Mol Cancer Ther; 16(11); 2563–71. ©2017 AACR .

中文翻译：

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T790M选择性EGFR-TKI联合达沙替尼是克服T790M阳性非小细胞肺癌EGFR-TKI耐药性的最佳策略

T790M突变选择性EGFR酪氨酸激酶抑制剂（EGFR-TKI）已在具有T790M突变的非小细胞肺癌（NSCLC）患者中显示出临床益处，这是抵抗EGFR-TKI的主要原因。然而，它们的功效是有限的，可能是由于在T790M阳性NSCLC中出现了细胞凋亡抗性。我们先前将Src家族激酶与T790M一起确定为致癌驱动因子，并发现Src抑制剂dasatinib与不可逆或临床前T790M选择性EGFR-TKI结合可增强T790M阳性细胞的抗肿瘤活性。在本研究中，我们评估了达沙替尼联合临床相关的T790M选择性EGFR-TKI ASP8273或奥西替尼在EGFR突变阳性NSCLC中是否伴有T790M突变的疗效。细胞活力测定表明，达沙替尼与这些TKI在T790M阳性细胞中具有协同作用，同时抑制了Src，Akt和Erk，这些药物在单药治疗后仍保持激活状态。如通过膜联蛋白-V结合试验所确定的，达沙替尼还增加了由T790M选择性EGFR-TKIs诱导的T790M阳性细胞的凋亡率；这与抗凋亡Bcl-2家族成员Bcl-xL的下调有关，这一发现在携带T790M阳性异种移植物的小鼠中得到了证实。我们的结果表明，Bcl-xL在T790M阳性NSCLC的细胞凋亡抗性中起关键作用，而达沙替尼联合临床相关的T790M选择性EGFR-TKIs可能有效克服NSCLC患者对第一代EGFR-TKIs的耐药性购买了T790M。分子癌疗法；16（11）; 2563–71。©2017 AACR。