Weill Cornell Medicine, New York, NY 10065, USA.
Centro de Investigaciones Biológicas Margarita Salas, Madrid, Spain.
Dev Cell. 2021 Dec 6;56(23):3264-3275.e7. doi: 10.1016/j.devcel.2021.09.023. Epub 2021 Oct 20.
Taxanes are widely used cancer chemotherapeutics. However, intrinsic resistance limits their efficacy without any actionable resistance mechanism. We have discovered a microtubule (MT) plus-end-binding CLIP-170 protein variant, hereafter CLIP-170S, which we found enriched in taxane-resistant cell lines and patient samples. CLIP-170S lacks the first Cap-Gly motif, forms longer comets, and impairs taxane access to its MT luminal binding site. CLIP-170S knockdown reversed taxane resistance in cells and xenografts, whereas its re-expression led to resistance, suggesting causation. Using a computational approach in conjunction with the connectivity map, we unexpectedly discovered that Imatinib was predicted to reverse CLIP-170S-mediated taxane resistance. Indeed, Imatinib treatment selectively depleted CLIP-170S, thus completely reversing taxane resistance. Other RTK inhibitors also depleted CLIP-170S, suggesting a class effect. Herein, we identify CLIP-170S as a clinically prevalent variant that confers taxane resistance, whereas the discovery of Imatinib as a CLIP-170S inhibitor provides novel therapeutic opportunities for future trials.
紫杉醇类药物广泛用于癌症的化学治疗。然而，内在的耐药性限制了它们的疗效，而没有任何可操作的耐药机制。我们发现了一种微管（MT）末端结合 CLIP-170 蛋白变体，以下简称 CLIP-170S，它在紫杉醇耐药细胞系和患者样本中丰富。CLIP-170S 缺乏第一个 Cap-Gly 基序，形成更长的彗星，并损害紫杉醇进入其 MT 内腔结合位点的能力。CLIP-170S 的敲低逆转了细胞和异种移植物中的紫杉醇耐药性，而其重新表达导致耐药性，表明其因果关系。我们使用计算方法结合连接组学，出乎意料地发现伊马替尼被预测可以逆转 CLIP-170S 介导的紫杉醇耐药性。事实上，伊马替尼治疗选择性地耗尽了 CLIP-170S，从而完全逆转了紫杉醇耐药性。其他 RTK 抑制剂也耗尽了 CLIP-170S，表明存在一类效应。在此，我们确定 CLIP-170S 是一种临床常见的变体，赋予紫杉醇耐药性，而发现伊马替尼是 CLIP-170S 的抑制剂为未来的试验提供了新的治疗机会。
