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Ref Type Journal Article
PMID (32234759)
Authors 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, Yan C, Kelley MC, Kauffmann RM, Hooks M, Grau A, Johnson DB, Vilgelm AE, Richmond A
Title Metastatic Melanoma Patient-Derived Xenografts Respond to MDM2 Inhibition as a Single Agent or in Combination with BRAF/MEK Inhibition.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 26
Issue 14
Date 2020 Jul 15
URL
Abstract Text 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.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 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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
KRT-232 KRT 232|KRT232|AMG232|AMG 232|AMG-232|Navtemadlin MDM2 Inhibitor 20 KRT-232 (AMG 232) is a potent inhibitor of the MDM2-p53 interaction, and inhibits proliferation of tumor cells in a p53 dependent manner (PMID: 24456472, PMID: 32234759).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
TP53 T140S missense unknown TP53 T140S lies within the DNA-binding domain of the Tp53 protein (PMID: 21760703). T140S has been identified in the scientific literature (PMID: 32234759), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Feb 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E melanoma predicted - sensitive Dabrafenib + KRT-232 + Trametinib Preclinical - Pdx Actionable In a preclinical study, the addition of KRT-232 (AMG 232) to the combination treatment of Tafinlar (dabrafenib) and Mekinist (trametinib) resulted in a synergistic effect, leading to a greater decrease in tumor growth and tumor size compared to either KRT-232 (AMG 232) alone or Tafinlar (dabrafenib) plus Mekinist (trametinib) in patient-derived xenograft (PDX) models of melanoma harboring BRAF V600E (PMID: 32234759). 32234759
BRAF V600E melanoma predicted - resistant KRT-232 Preclinical - Pdx Actionable In a preclinical study, patient-derived xenograft (PDX) models of melanoma harboring BRAF V600E demonstrated resistance to treatment with KRT-232 (AMG 232) (PMID: 32234759). 32234759
BRAF V600E melanoma sensitive KRT-232 + Navitoclax Preclinical - Pdx Actionable In a preclinical study, the combination of KRT-232 (AMG 232) and Navitoclax (ABT-263) resulted in a greater response than either drug alone in patient-derived xenograft (PDX) models of melanoma harboring BRAF V600E, leading to tumor regression (PMID: 32234759). 32234759