Notch signaling is aberrantly activated in approximately one third of non–small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor, and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin [mean combination index (CI) value, 0.54 and 0.85, respectively, P = 0.01]. On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI, 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line– and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel and that wild-type KRAS and BRAF status may predict better patient response to the combination therapy. Mol Cancer Ther; 16(12); 2759–69. ©2017 AACR.

中文翻译：

---

BMS-906024 抑制伽马分泌酶可增强紫杉醇在肺腺癌中的疗效

Notch 信号在大约三分之一的非小细胞肺癌 (NSCLC) 中被异常激活。我们表征了 BMS-906024（一种临床相关的 Notch γ 分泌酶抑制剂）与 NSCLC 临床前模型中的一线化疗之间的相互作用。对 14 个人类 NSCLC 细胞系进行了化学敏感性测定。BMS-906024 和紫杉醇之间的协同作用明显高于 BMS-906024 和顺铂 [平均联合指数 (CI) 值，分别为 0.54 和 0.85，P = 0.01]。在 31 个非小细胞肺癌细胞系的扩展组中，其中 25 个是腺癌，BMS-906024 和紫杉醇在 KRAS 和 BRAF 野生型中的协同作用显着高于 KRAS 或 BRAF 突变细胞（平均 CI，0.43 对 0.90 ，分别；P = 0.003）。紫杉醇诱导的 Notch1 激活与 KRAS 或 BRAF 突变组中 BMS-906024 和紫杉醇之间的协同作用有关。在杂合 KRAS 突变细胞系中，突变 KRAS 的敲除增加了 BMS-906024 和紫杉醇之间的协同作用。在 KRAS 或 BRAF 突变的 NSCLC 中，协同作用与突变或无效 TP53 状态之间以及协同作用与低 H2O2 通路特征之间存在显着相关性。外源性过表达激活的 Notch1 或 Notch3 对 BMS-906024 增强的 NSCLC 对紫杉醇的敏感性没有影响。使用细胞系和患者来源的肺腺癌异种移植物进行的体内研究证实，通过降低细胞增殖和增加细胞凋亡，BMS-906024 加紫杉醇与单独使用任一药物相比，抗肿瘤活性增强。这些结果表明 BMS-906024 使 NSCLC 对紫杉醇敏感，并且野生型 KRAS 和 BRAF 状态可以预测患者对联合治疗的更好反应。摩尔癌症治疗; 16(12); 2759-69。©2017 AACR。