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 23	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
BRAF	S147N	missense	unknown	BRAF S147N does not lie within any known functional domains of the Braf protein (UniProt.org). S147N has been identified in the scientific literature (PMID: 34759319, PMID: 32234759), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Aug 2024).
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	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
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