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 联合达沙替尼作为克服 T790M 阳性非小细胞肺癌 EGFR-TKI 耐药的最佳策略

T790M 突变选择性 EGFR 酪氨酸激酶抑制剂 (EGFR-TKI) 已证明对携带 T790M 突变的非小细胞肺癌 (NSCLC) 患者具有临床益处，这是对 EGFR-TKI 耐药的主要原因。然而，它们的功效是有限的，可能是由于 T790M 阳性 NSCLC 中出现细胞凋亡抗性。我们之前将 Src 家族激酶与 T790M 一起确定为共生驱动因素，并发现 Src 抑制剂达沙替尼与不可逆或临床前 T790M 选择性 EGFR-TKI 结合增强了 T790M 阳性细胞的抗肿瘤活性。在目前的研究中，我们评估了达沙替尼联合临床相关的 T790M 选择性 EGFR-TKI ASP8273 或奥希替尼在有或没有 T790M 突变的 EGFR 突变阳性 NSCLC 中的疗效。细胞活力测定表明，达沙替尼在 T790M 阳性细胞中与这些 TKI 具有协同作用，并同时抑制 Src、Akt 和 Erk，它们在单药治疗后仍保持激活状态。达沙替尼还增加了 T790M 选择性 EGFR-TKI 诱导的 T790M 阳性细胞的凋亡率，这是通过 Annexin-V 结合测定确定的；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证实。我们的结果表明，Bcl-xL 在 T790M 阳性 NSCLC 的细胞凋亡耐药中起关键作用，达沙替尼联合临床相关的 T790M 选择性 EGFR-TKI 可能有效克服 NSCLC 患者对第一代 EGFR-TKI 的耐药性与收购的 T790M。摩尔癌症治疗; 16(11); 2563-71。©2017 AACR。