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

• Published in: Clinical cancer research 2020-07, Vol.26 (14), p.3803-3818
• Main Authors: Shattuck-Brandt, Rebecca L, Chen, Sheau-Chiann, Murray, Emily, Johnson, Christopher Andrew, Crandall, Holly, O'Neal, Jamye F, Al-Rohil, Rami Nayef, Nebhan, Caroline A, Bharti, Vijaya, Dahlman, Kimberly B, Ayers, Gregory D, Yan, Chi, Kelley, Mark C, Kauffmann, Rondi M, Hooks, Mary, Grau, Ana, Johnson, Douglas B, Vilgelm, Anna E, Richmond, Ann
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cell Line, Tumor; Female; Humans; Male; MAP Kinase Signaling System - drug effects; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Mice; Middle Aged; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Mutation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteolysis - drug effects; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Tumor Suppressor Protein p53 - metabolism; Ubiquitination - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1895

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 mutation status, but no available agents are available for , and mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to or mutations, while loss or mutation of 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 tumors responded to KRT-232 treatment alone while 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 or PAN melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAF -mutant tumors.