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Metastatic Melanoma Patient-derived Xenografts Respond to MDM2 Inhibition as a Single Agent or in Combination with BRAF/MEK Inhibition.

转移性黑色素瘤患者来源的异种移植物对 MDM2 抑制作为单药或与 BRAF/MEK 抑制联合反应。

  • 影响因子:8.32
  • DOI:10.1158/1078-0432.CCR-19-1895
  • 作者列表:"Shattuck-Brandt RL","Chen SC","Murray E","Johnson CA","Crandall H","O'Neal JF","Al-Rohil RN","Nebhan CA","Bharti V","Dahlman KB","Ayers GD","Kelley MC","Kauffman RM","Hooks M","Grau A","Johnson DB","Vilgelm AE","Richmond A
  • 发表时间:2020-03-31
Abstract

PURPOSE:Over 60% of melanoma patients 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, 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 ~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 melanoma patients. 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:100% 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 PANwt(BRAFwt, NRASwt) TP53WT melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may an effective treatment strategy for BRAFV600 mutant tumors.

摘要

目的: 超过 60% 的黑色素瘤患者对免疫检查点抑制剂 (ICI) 治疗有反应,但随后这些治疗有许多进展。二线靶向治疗基于 BRAF 突变状态,但 NRAS 、 CDKN2A 、 PTEN 和 TP53 突变尚无可用的药物。超过 70% 的黑色素瘤由于 BRAF 或 NRAS 突变而激活 MAPK 通路,而约 40% 的黑色素瘤发生 cdkn2a 缺失或突变,导致 MDM2-mediated 泛素化和 p53 降解。在这里,我们研究了阻止 P53 的 MDM2 泛素化的 MDM2 抑制剂对黑色素瘤中 P53 的过度 MDM2-mediated 降解的治疗效果,单独使用 MDM2 抑制剂或联合 MAPK 靶向治疗治疗荷瘤小鼠。 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 例黑色素瘤患者建立了患者来源的异种移植 (PDX)。用 KRT-232 或 BRAF 和/或 MEK 抑制剂联合治疗小鼠。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: 100% 的 15 个 PDX 肿瘤表现出显著的生长抑制,无论是对 KRT-232 单独或与 BRAF 和/或 MEK 抑制剂联合反应。只有 BRAFV600wt 肿瘤对 KRT-232 单独治疗有反应,而 BRAFV600E/M PDXs 对 KRT-232 和 BRAF/MEK 抑制剂的联合治疗表现出协同反应。 结论: KRT-232 是治疗 BRAFwt 或 PANwt(BRAFwt,NRASwt) TP53WT 黑色素瘤的有效方法。联合 BRAF 和/或 MEK 抑制剂,KRT-232 可能是 BRAFV600 突变肿瘤的有效治疗策略。

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