Abstract: A major challenge of targeted cancer therapy is the selection for drug‐resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is central regulator of protein homeostasis and a promising anticancer target because of its vital role in cell growth and survival. One ATP‐competitive p97 inhibitor, CB‐5083, has entered clinical trials. Selective pressure on HCT116 cells dosed with CB‐5083 identified five different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB‐5083 resistant p97 mutants, N660 K and T688 A, were also resistant to several other ATP‐competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS‐873 and UPCDC‐30245 were unaffected by these mutations. We also established a CB‐5083 resistant cell line that harbors a new p97 double mutation (D649 A/T688 A). While CB‐5083, NMS‐873, and UPCDC‐30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS‐873 and UPCDC‐30245 were 30‐fold more potent in inhibiting the CB‐5083 resistant D649 A/T688 A double mutant than CB‐5083. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP‐competitive p97 inhibitors arises during anticancer treatment.

中文翻译：

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变构 p97 抑制剂可以克服对 ATP 竞争性 p97 抑制剂的抗性，用于潜在的抗癌治疗

摘要: 靶向癌症治疗的一个主要挑战是选择肿瘤细胞中的耐药突变导致治疗效果丧失。p97/VCP 是蛋白质稳态的中心调节因子，也是一个很有前途的抗癌靶点，因为它在细胞生长和存活中起着至关重要的作用。一种 ATP 竞争性 p97 抑制剂 CB-5083 已进入临床试验。用 CB-5083 对 HCT116 细胞施加的选择性压力确定了五种不同的抗性突变体。鉴定具有不同作用机制的 p97 抑制剂将提供克服这类耐药突变的潜力。我们的结果表明，两个 CB-5083 耐药 p97 突变体 N660 K 和 T688 A 也对其他几种 ATP 竞争性 p97 抑制剂具有耐药性，而两种变构 p97 抑制剂 NMS-873 和 UPCDC-30245 的抑制不受这些突变的影响。我们还建立了一个含有新的 p97 双突变 (D649 A/T688 A) 的 CB-5083 抗性细胞系。虽然 CB-5083、NMS-873 和 UPCDC-30245 均能有效抑制亲本 HCT116 细胞系的增殖，但 NMS-873 和 UPCDC-30245 在抑制 CB-5083 抗性 D649 A/T688 A 双倍方面的效力要高出 30 倍比 CB-5083 突变。我们的研究结果表明，当抗癌治疗期间出现对 ATP 竞争性 p97 抑制剂的耐药性时，变构 p97 抑制剂是有希望的替代品。NMS-873 和 UPCDC-30245 在抑制 CB-5083 抗性 D649 A/T688 A 双突变体方面的效力是 CB-5083 的 30 倍。我们的研究结果表明，当抗癌治疗期间出现对 ATP 竞争性 p97 抑制剂的耐药性时，变构 p97 抑制剂是有希望的替代品。NMS-873 和 UPCDC-30245 在抑制 CB-5083 抗性 D649 A/T688 A 双突变体方面的效力是 CB-5083 的 30 倍。我们的研究结果表明，当抗癌治疗期间出现对 ATP 竞争性 p97 抑制剂的耐药性时，变构 p97 抑制剂是有希望的替代品。