Purpose: Over 60% of patients with melanoma respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on BRAF mutation status, but no available agents are available for NRAS, NF1, CDKN2A, PTEN , and TP53 mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to BRAF or NRAS mutations, while loss or mutation of CDKN2A occurs in approximately 40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of p53. Here, we investigated the therapeutic efficacy of over-riding MDM2-mediated degradation of p53 in melanoma with an MDM2 inhibitor that interrupts MDM2 ubiquitination of p53, treating tumor-bearing mice with the MDM2 inhibitor alone or combined with MAPK-targeted therapy. Experimental Design: To characterize the ability of the MDM2 antagonist, KRT-232, to inhibit tumor growth, we established patient-derived xenografts (PDX) from 15 patients with melanoma. Mice were treated with KRT-232 or a combination with BRAF and/or MEK inhibitors. Tumor growth, gene mutation status, as well as protein and protein–phosphoprotein changes, were analyzed. Results: One-hundred percent of the 15 PDX tumors exhibited significant growth inhibition either in response to KRT-232 alone or in combination with BRAF and/or MEK inhibitors. Only BRAFV600WT tumors responded to KRT-232 treatment alone while BRAFV600E/M PDXs exhibited a synergistic response to the combination of KRT-232 and BRAF/MEK inhibitors. Conclusions: KRT-232 is an effective therapy for the treatment of either BRAFWT or PAN WT (BRAFWT, NRASWT) TP53WT melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAFV600-mutant tumors.

中文翻译：

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转移性黑色素瘤患者来源的异种移植物对 MDM2 抑制作为单一药物或与 BRAF/MEK 抑制联合使用有反应。

目的：超过 60% 的黑色素瘤患者对免疫检查点抑制剂 (ICI) 疗法有反应，但许多人随后在这些疗法中取得进展。二线靶向治疗基于 BRAF 突变状态，但没有可用于 NRAS、NF1、CDKN2A、PTEN 和 TP53 突变的药物。由于 BRAF 或 NRAS 突变，超过 70% 的黑色素瘤肿瘤激活了 MAPK 通路，而大约 40% 的黑色素瘤发生 CDKN2A 缺失或突变，导致不受调节的 MDM2 介导的泛素化和 p53 降解。在这里，我们研究了使用 MDM2 抑制剂抑制黑色素瘤中 MDM2 介导的 p53 降解的治疗效果，该抑制剂会中断 p53 的 MDM2 泛素化，单独使用 MDM2 抑制剂或与 MAPK 靶向治疗联合治疗荷瘤小鼠。实验设计：为了表征 MDM2 拮抗剂 KRT-232 抑制肿瘤生长的能力，我们从 15 名黑色素瘤患者中建立了患者来源的异种移植物 (PDX)。用 KRT-232 或与 BRAF 和/或 MEK 抑制剂的组合治疗小鼠。分析了肿瘤生长、基因突变状态以及蛋白质和蛋白质-磷蛋白的变化。结果：15 种 PDX 肿瘤中有 100% 对单独的 KRT-232 或与 BRAF 和/或 MEK 抑制剂的联合反应表现出显着的生长抑制。只有 BRAFV600WT 肿瘤对单独的 KRT-232 治疗有反应，而 BRAFV600E/M PDX 对 KRT-232 和 BRAF/MEK 抑制剂的组合表现出协同反应。结论：KRT-232 是治疗 BRAFWT 或 PAN WT（BRAFWT，NRASWT）TP53WT 黑色素瘤的有效疗法。