Paradoxical activation of c-Src as a drug-resistant mechanism
Paradoxical activation of c-Src as a drug-resistant mechanism
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DOI：
10.1016/j.celrep.2021.108876
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发表时间：
2021-03-23
期刊：
影响因子：
8.8
通讯作者：
Watanabe, Naoki
中科院分区：
文献类型：
--
作者：
Higuchi, Makio;Ishiyama, Kenichi;Watanabe, Naoki
ATP竞争性抑制剂已被开发为有前途的抗癌剂。然而，耐药性经常发生，其潜在机制尚未完全了解。在这里，我们表明，c-Src及其下游磷酸化级联的激活可以矛盾地诱导Src靶向和RTK靶向激酶抑制剂。我们发现，抑制剂结合诱导c-Src的构象变化，导致协会的活性形式c-Src与粘着斑激酶（FAK）。抑制剂浓度的降低导致抑制剂从c-Src-FAK复合物解离，这允许c-Src磷酸化FAK并启动FAK-Grb 2介导的Erk信号传导。此外，c-Src中的耐药突变降低了c-Src抑制剂的亲和力，通过增强c-Src突变细胞中FAK和Erk的磷酸化，将Src抑制剂转化为细胞增殖的促进剂。因此，我们的数据揭示了靶向激酶抑制剂引起的细胞生长的矛盾增强，为未来开发有效和安全的癌症治疗提供了潜在的重要线索。
ATP-competitive inhibitors have been developed as promising anti-cancer agents. However, drug-resistance frequently occurs, and the underlying mechanisms are not fully understood. Here, we show that the activation of c-Src and its downstream phosphorylation cascade can be paradoxically induced by Src-targeted and RTK-targeted kinase inhibitors. We reveal that inhibitor binding induces a conformational change in c-Src, leading to the association of the active form c-Src with focal adhesion kinase (FAK). Reduction of the inhibitor concentration results in the dissociation of inhibitors from the c-Src-FAK complex, which allows c-Src to phosphorylate FAK and initiate FAK-Grb2-mediated Erk signaling. Furthermore, a drug-resistant mutation in c-Src, which reduces the affinity of inhibitors for c-Src, converts Src inhibitors into facilitators of cell proliferation by enhancing the phosphorylation of FAK and Erk in c-Src-mutated cells. Our data thus reveal paradoxical enhancement of cell growth evoked by target-based kinase inhibitors, providing potentially important clues for the future development of effective and safe cancer treatment.