Non-Small-Cell Lung Cancer (NSCLC) is a poorly chemosensitive tumor and targeted therapies are only used for about 15% of patients where a specific driving and druggable lesion is observed (EGFR, ALK, ROS). KRAS is one of the most frequently mutated genes in NSCLC and patients harboring these mutations do not benefit from specific treatments. Sorafenib, a multi-target tyrosine kinase inhibitor, was proposed as a potentially active drug in KRAS-mutated NSCLC patients, but clinical trials results were not conclusive. Here we show that the NSCLC cells' response to sorafenib depends on the type of KRAS mutation. KRAS G12V cells respond less to sorafenib than the wild-type counterpart, in vitro and in vivo. To overcome this resistance, we used high-throughput screening with a siRNA library directed against 719 human kinases, and Wee1 was selected as a sorafenib response modulator. Inhibition of Wee1 by its specific inhibitor MK1775 in combination with sorafenib restored the KRAS mutated cells' response to the multi-target tyrosine kinase inhibitor. This combination of the Wee1 inhibitor with sorafenib, if confirmed in models with different genetic backgrounds, might be worth investigating further as a new strategy for KRAS mutated NSCLC.

中文翻译：

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Wee1抑制剂MK1775使KRAS突变的NSCLC细胞对索拉非尼敏感。

非小细胞肺癌（NSCLC）是一种化学敏感性较差的肿瘤，仅在约15％观察到特定驱动和可药物治疗的病变（EGFR，ALK，ROS）的患者中使用靶向疗法。KRAS是NSCLC中最常见的突变基因之一，具有这些突变的患者无法从特定治疗中受益。Sorafenib是一种多靶点酪氨酸激酶抑制剂，被提议作为KRAS突变的NSCLC患者的潜在活性药物，但临床试验结果尚无定论。在这里，我们显示NSCLC细胞对索拉非尼的反应取决于KRAS突变的类型。在体外和体内，KRAS G12V细胞对索拉非尼的反应要比野生型对应物少。为了克服这种抗药性，我们使用了针对719种人类激酶的siRNA文库进行高通量筛选，Wee1被选为索拉非尼应答调节剂。其特异性抑制剂MK1775与索拉非尼联合抑制Wee1恢复了KRAS突变细胞对多靶酪氨酸激酶抑制剂的反应。如果在具有不同遗传背景的模型中证实了Wee1抑制剂与索拉非尼的这种组合，则可能值得进一步研究，作为KRAS突变NSCLC的新策略。