原理:KIT中的突变,一个主要的癌症驱动基因,现在被认为是治疗由粘膜和肢端组织以及慢性阳光损伤部位引起的黑色素瘤的重要药物靶标。目前,伊马替尼是美国国家综合癌症网络(NCCN)临床实践指南推荐的唯一针对KIT突变黑素瘤的靶向药物.有KIT突变的患者,然而,对伊马替尼不敏感或进展迅速,这限制了其临床应用。因此,迫切需要有效的KIT突变黑素瘤抑制剂。方法:一组来自具有KIT突变的黑色素瘤患者的患者源性肿瘤异种移植(PDX)模型和相应的PDX衍生细胞(PDC)(KITV560D,建立了KITK642E和KITD816V),characterized,然后用于体外测试,随后,一组已知KIT抑制剂的体内抑制作用。结果:Ponatinib对携带KIT突变的细胞比伊马替尼更有效。体内药效评估实验表明,与伊马替尼相比,普纳替尼治疗对携带KIT突变的黑素瘤的抑制作用更强。机械上,分子动力学(MD)模拟揭示了一个合理的原子级解释,即与伊马替尼相比,普纳替尼对KITD816V突变蛋白具有更高的亲和力.结论:我们对带有KIT突变和KITWT的黑素瘤的研究表明,对于带有KIT突变的黑素瘤,ponatinib是一种比伊马替尼更有效的抑制剂,因此强调了ponatinib应优先考虑设计针对患有KIT突变的黑色素瘤患者的精确治疗。此外,我们的工作为开展临床试验以检查ponatinib的再利用提供了理由,已经被批准用于白血病,用于治疗大部分黑色素瘤患者。
Rationale: Mutations in KIT, a major cancer driver gene, are now considered as important drug targets for the treatment of
melanomas arising from mucosal and acral tissues and from chronically sun-damaged sites. At present, imatinib is the only targeted drug for KIT-mutation-bearing
melanomas that is recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines. Patients with KIT mutations, however, are either insensitive or rapidly progress to imatinib insensitivity, which restricts its clinical use. Thus, effective inhibitors of KIT-mutation-bearing
melanomas are urgently needed. Methods: A cohort of patient-derived tumor xenograft (PDX) models and corresponding PDX-derived cells (PDCs) from patients with melanomas harboring KIT mutations (KIT V560D, KIT K642E and KIT D816V) were established, characterized, and then used to test the in vitro and, subsequently, in vivo inhibitory effects of a panel of known KIT inhibitors. Results: Ponatinib was more potent than imatinib against cells bearing KIT mutations. In vivo drug efficacy evaluation experiments showed that ponatinib treatment caused much stronger inhibition of KIT-mutation-bearing melanomas than did imatinib. Mechanistically, molecular dynamics (MD) simulations revealed a plausible atomic-level explanation for the observation that ponatinib has a higher affinity for the KIT D816V mutant protein than does imatinib. Conclusions: Our study of KIT-mutation-and KIT WT-bearing
melanomas demonstrates that ponatinib is a far more potent inhibitor than is imatinib for KIT-mutation-bearing
melanomas and thus underscores that ponatinib should be given priority consideration for the design of precision treatments for melanoma patients triaged to have KIT mutations. Moreover, our work provides a rationale for undertaking clinical trials to examine the repurposing of ponatinib, which is already approved for use in leukemia, for use in treating a large subset of melanoma patients.