The combination of chemotherapy and targeted therapy has been validated in non-small-cell lung cancer (NSCLC) patients withEGFRmutations. We therefore investigated whether this type of combined approach could be more widely used by targeting other genetic alterations present in NSCLC. PDXs were generated from patients with NSCLC adenocarcinomas (ADCs) and squamous-cell carcinomas (SCCs). Targeted NGS analyses identified various molecular abnormalities in the MAPK and PI3K pathways and in the cell cycle process in our PDX panel. The antitumor efficacy of targeted therapies alone or in combination with chemotherapy was then tested in vivo. We observed that trametinib, BKM120, AZD2014 and palbociclib increased the efficacy of each chemotherapy in SCC PDXs, in contrast to a non-insignificant or slight improvement in ADCs. Furthermore, we observed high efficacy of trametinib inKRAS-,HRAS- andNRAS-mutated tumors (ADCs and SCCs), suggesting that the MEK inhibitor may be useful in a wider population of NSCLC patients, not just those withKRAS-mutated ADCs. Our results suggest that the detection of pathogenic variants by NGS should be performed in all NSCLCs, and particularly in SCCs, to offer patients a more effective combination of chemotherapy and targeted therapy.
化疗与靶向治疗的联合应用已在携带EGFR突变的非小细胞肺癌（NSCLC）患者中得到验证。因此，本研究探讨通过靶向NSCLC中存在的其他基因变异，是否可扩大此类联合疗法的适用范围。我们利用NSCLC腺癌（ADCs）和鳞状细胞癌（SCCs）患者样本构建了人源肿瘤异种移植模型（PDXs）。靶向二代测序分析在PDX模型组中检测到MAPK通路、PI3K通路及细胞周期过程中的多种分子异常。随后通过体内实验评估了靶向药物单用或联合化疗的抗肿瘤疗效。结果显示，曲美替尼、BKM120、AZD2014和帕博西尼在SCC PDXs中显著增强了各类化疗药物的疗效，而在ADCs中仅观察到轻微或不显著的改善。值得注意的是，曲美替尼对携带KRAS、HRAS及NRAS突变的肿瘤（包括ADCs和SCCs）均表现出高效抑制作用，提示MEK抑制剂可能适用于更广泛的NSCLC患者群体，而不仅限于KRAS突变的腺癌患者。本研究结果表明，应对所有NSCLC（尤其是鳞状细胞癌）进行二代测序以检测致病性变异，从而为患者提供更有效的化疗与靶向联合治疗方案。
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