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

Abstract

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 <i>BRAF</i> mutation status, but no available agents are available for <i>NRAS, NF1, CDKN2A, PTEN</i>, and <i>TP53</i> mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to <i>BRAF</i> or <i>NRAS</i> mutations, while loss or mutation of <i>CDKN2A</i> 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. 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. 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 <i>BRAF^V600WT</i> tumors responded to KRT-232 treatment alone while <i>BRAF^V600E/M</i> PDXs exhibited a synergistic response to the combination of KRT-232 and BRAF/MEK inhibitors. KRT-232 is an effective therapy for the treatment of either <i>BRAF^WT</i> or PAN ^<i>WT</i> <i>(BRAF^WT, NRAS^WT) TP53^WT</i> melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAF^V600-mutant tumors.