肺癌是一个重要的全球健康问题,是全球癌症相关死亡的主要原因。肺癌中特定基因组改变如EGFR和KRAS的鉴定为靶向治疗的发展铺平了道路。虽然靶向治疗显示EGFR的肺癌,MET和ALK突变已经建立,RET突变的选择仍然有限.重要的是,已发现RET突变与其他基因组突变相互排斥,并且与脑转移的高发生率相关。鉴于这些事实,探索RET靶向治疗的发展以及阐明RET表达肺癌细胞转移的潜在机制势在必行.在这项研究中,我们研究了PLM-101,一种新型的RET/YES1双靶点抑制剂,它对CCDC6-RET阳性癌细胞表现出显著的抗癌活性和对YES1阳性癌细胞的抗转移作用.我们的发现揭示了YES1-Cortactin-actin重塑途径在肺癌细胞转移中的意义。建立YES1作为抑制转移的有希望的靶标。本文揭示了一种有效靶向RET和YES1的新型抑制剂,从而证明了其阻止RET重排肺癌生长和转移的潜力。
Lung cancer represents a significant global health concern and stands as the leading cause of cancer-related mortality worldwide. The identification of specific genomic alterations such as EGFR and KRAS in lung cancer has paved the way for the development of targeted therapies. While targeted therapies for lung cancer exhibiting EGFR, MET and ALK mutations have been well-established, the options for RET mutations remain limited. Importantly, RET mutations have been found to be mutually exclusive from other genomic mutations and to be related with high incidences of brain metastasis. Given these facts, it is imperative to explore the development of RET-targeting therapies and to elucidate the mechanisms underlying metastasis in RET-expressing lung cancer cells. In this study, we investigated PLM-101, a novel dual-target inhibitor of RET/YES1, which exhibits notable anti-cancer activities against CCDC6-RET-positive cancer cells and anti-metastatic effects against YES1-positive cancer cells. Our findings shed light on the significance of the YES1-Cortactin-actin remodeling pathway in the metastasis of lung cancer cells, establishing YES1 as a promising target for suppression of metastasis. This paper unveils a novel inhibitor that effectively targets both RET and YES1, thereby demonstrating its potential to impede the growth and metastasis of RET rearrangement lung cancer.