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

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 BRAFwtor PANwt (BRAFwt, NRASwt) TP53WTmelanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may an effective treatment strategy for BRAFV600 mutant tumors.