Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	26	14	2020 Jul 15	3803-3818	Clin Cancer Res

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
KRT-232	KRT-232	15	11

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
KRT-232		KRT 232\|KRT232\|AMG232\|AMG 232\|AMG-232\|Navtemadlin	MDM2 Inhibitor 22	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, Sep 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