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|Ref Type||Journal Article|
|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|
|Date||2020 Jul 15|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|KRT-232||KRT 232|KRT232|AMG232|AMG 232|AMG-232|Navtemadlin||MDM2 Inhibitor 21||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, Mar 2023).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|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||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||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|