Protein tyrosine kinase 6 (PTK6), a non-receptor tyrosine kinase, is an oncogenic driver in many tumor types. However, agents that therapeutically target PTK6 are lacking. Although several PTK6 kinase inhibitors have been developed, none have been clinically translated, which may be due to kinase-independent functions that compromise their efficacy. PTK6 kinase inhibitor treatment phenocopies some, but not all effects of PTK6 downregulation. PTK6 downregulation inhibits growth of breast cancer cells, but treatment with PTK6 kinase inhibitor does not. To chemically downregulate PTK6, we designed a PROTAC, MS105, which potently and specifically degrades PTK6. Treatment with MS105, but not PTK6 kinase inhibitor, inhibits growth and induces apoptosis of breast cancer cells, phenocopying the effects of PTK6 (short hairpin RNA) shRNA/CRISPR. In contrast, both MS105 and PTK6 kinase inhibitor effectively inhibit breast cancer cell migration, supporting the differing kinase dependencies of PTK6’s oncogenic functions. Our studies support PTK6 degraders as a preferred approach to targeting PTK6 in cancer.

中文翻译：

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PROTAC 降解剂抑制 PTK6 诱导乳腺癌细胞凋亡的致癌功能


蛋白酪氨酸激酶 6 （PTK6） 是一种非受体酪氨酸激酶，是许多肿瘤类型的致癌驱动因素。然而，缺乏治疗性靶向 PTK6 的药物。尽管已经开发了几种 PTK6 激酶抑制剂，但尚未得到临床转化，这可能是由于激酶非依赖性功能损害了其疗效。PTK6 激酶抑制剂治疗表型复制 PTK6 下调的一些但不是全部作用。PTK6 下调抑制乳腺癌细胞的生长，但用 PTK6 激酶抑制剂治疗不会。为了化学下调 PTK6，我们设计了一种 PROTAC MS105，它可以有效和特异性地降解 PTK6。用 MS105 而不是 PTK6 激酶抑制剂处理，抑制乳腺癌细胞的生长并诱导细胞凋亡，表型复制 PTK6 （短发夹 RNA） shRNA/CRISPR 的作用。相比之下，MS105 和 PTK6 激酶抑制剂均能有效抑制乳腺癌细胞迁移，支持 PTK6 致癌功能的不同激酶依赖性。我们的研究支持 PTK6 降解剂作为靶向癌症中 PTK6 的首选方法。