Tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, resistance to these agents frequently occurs, and it is often related to the activation of the Hedgehog (Hh) and MET signaling cascades driving the epithelial-to-mesenchymal transition (EMT). Because the concomitant inhibition of both Hh and MET pathways restores the sensitivity to anti-EGFR drugs, here we aimed at discovering the first compounds that block simultaneously MET and SMO. By using an “in silico drug repurposing” approach and by validating our predictions both in vitro and in vivo, we identified a set of compounds with the desired dual inhibitory activity and enhanced antiproliferative activity on EGFR TKI-resistant NSCLC. The identification of the known MET TKIs, glesatinib and foretinib, as negative modulators of the Hh pathway, widens their application in the context of NSCLC.

中文翻译：

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双重MET和SMO负调节剂克服了人类非小细胞肺癌对EGFR抑制剂的耐药性。

EGF受体（EGFR）的酪氨酸激酶抑制剂（TKIs）已大大改善了非小细胞肺癌（NSCLC）的疾病预后。不幸的是，对这些药剂的抗性经常发生，并且通常与刺猬（Hh）和MET信号级联的激活有关，这些信号级联驱动上皮到间充质转变（EMT）。因为同时抑制Hh和MET通路可恢复对抗EGFR药物的敏感性，所以在此我们旨在发现首个同时阻断MET和SMO的化合物。通过使用“计算机内药物再利用”方法并通过验证我们的体内和体外预测，我们鉴定了一组具有所需的双重抑制活性和增强的对EGFR TKI耐药性NSCLC的抗增殖活性的化合物。