Melanoma remains the most aggressive and fatal form of skin cancer, despite several FDA-approved targeted chemotherapies and immunotherapies for use in advanced disease. Of the 100 350 new patients diagnosed with melanoma in 2020 in the US, more than half will develop metastatic disease leading to a 5-year survival rate <30%, with a majority of these developing drug-resistance within the first year of treatment. These statistics underscore the critical need in the field to develop more durable therapeutics as well as those that can overcome chemotherapy-induced drug resistance from currently approved agents. Fortunately, several of the drug-resistance pathways in melanoma, including the proteins in those pathways, rely in part on Hsp90 chaperone function. This presents a unique and novel opportunity to simultaneously target multiple proteins and drug-resistant pathways in this disease via molecular chaperone inhibition. Taken together, we hypothesize that our novel C-terminal Hsp90 inhibitor, KU758, in combination with the current standard of care targeted therapies (e.g. vemurafenib and cobimetinib) can both synergize melanoma treatment efficacy in BRAF-mutant tumors, as well as target and overcome several major resistance pathways in this disease. Using in vitro proliferation and protein-based Western Blot analyses, our novel inhibitor, KU758, potently inhibited melanoma cell proliferation (without induction of the heat shock response) in vitro and synergized with both BRAF and MEK inhibitors in inhibition of cell migration and protein expression from resistance pathways. Overall, our work provides early support for further translation of C-terminal Hsp90 inhibitor and mitogen-activated protein kinase pathway inhibitor combinations as a novel therapeutic strategy for BRAF-mutant melanomas.

中文翻译：

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一种新型 C 端 Hsp90 抑制剂 KU758 与 BRAF 或 MEK 抑制剂联合使用可增强疗效，并针对 BRAF 突变黑色素瘤的耐药途径。


尽管 FDA 批准了几种用于晚期疾病的靶向化疗和免疫疗法，但黑色素瘤仍然是最具侵袭性和致命性的皮肤癌。 2020 年，美国将有 100 350 名新诊断出黑色素瘤的患者，其中一半以上将出现转移性疾病，导致 5 年生存率为 <30%，其中大多数在治疗的第一年内出现耐药性。这些统计数据强调了该领域迫切需要开发更持久的治疗方法以及能够克服目前批准的药物化疗引起的耐药性的治疗方法。幸运的是，黑色素瘤中的一些耐药途径，包括这些途径中的蛋白质，部分依赖于 Hsp90 伴侣功能。这提供了一个独特而新颖的机会，可以通过分子伴侣抑制同时靶向该疾病中的多种蛋白质和耐药途径。综上所述，我们假设我们的新型 C 端 Hsp90 抑制剂 KU758 与当前标准护理靶向治疗（例如维莫非尼和考比替尼）相结合，既可以协同增强 BRAF 突变肿瘤中黑色素瘤的治疗功效，又可以靶向和克服这种疾病的几个主要耐药途径。使用体外增殖和基于蛋白质的蛋白质印迹分析，我们的新型抑制剂 KU758 在体外有效抑制黑色素瘤细胞增殖（不诱导热休克反应），并与 BRAF 和 MEK 抑制剂协同抑制细胞迁移和蛋白质表达来自阻力途径。 总体而言，我们的工作为 C 端 Hsp90 抑制剂和丝裂原激活蛋白激酶途径抑制剂组合的进一步转化作为 BRAF 突变黑色素瘤的新型治疗策略提供了早期支持。