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Ref Type Journal Article
PMID (28498808)
Authors Chen H, Luo D, Zhang L, Lin X, Luo Q, Yi H, Wang J, Yan X, Li B, Chen Y, Liu X, Zhang H, Liu S, Qiu M, Yang D, Jiang N
Title Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells.
Journal Oncotarget
Vol
Issue
Date 2017 Apr 24
URL
Abstract Text Dedifferentiated papillary thyroid cancer (DePTC) is characterized by aggressive growth, recurrence, distant metastasis, and resistance to radioactive iodine (RAI) therapy. DePTC is also accompanied by poor prognosis and high early-mortality. Nevertheless, most DePTC cells show intact p53 downstream functionality. In cells with wild-type p53, the murine double minute2 (MDM2) protein interacts with p53 and abrogates its activity. Inhibition of the MDM2-p53 interaction restores p53 activity and leads to cell cycle arrest and apoptosis. Restoring p53 function by inhibiting its interaction with p53 suppressors such as MDM2 is thus a promising therapeutic strategy for the treatment of DePTC. The novel MDM2-p53 interaction antagonist APG115 is an analogue of SAR405838, and is being tested in a phase I clinical trial. In this study, we evaluated the efficacy of APG115 as a single-agent to treat DePTC. APG115 diminished the viability of p53 wild-type DePTC cells and induced cell cycle arrest and apoptosis. In a human xenograft mouse model, APG115 elicited robust tumor regression and cell apoptosis. These data demonstrate that further research is warranted to determine whether APG115 can be used to effectively treat DePTC patients.

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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
APG-115 APG-115 1 4
Drug Name Trade Name Synonyms Drug Classes Drug Description
APG-115 APG115|APG 115|Alrizomadlin MDM2 Inhibitor 20 APG-115, a derivative of SAR405838, inhibits MDM2 and its interaction with p53, thereby stabilizing and activating wild-type p53, which may result in antitumor activity and also synergizes with PD-1 inhibitors (PMID: 28498808, PMID: 31779710).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 wild-type thyroid gland papillary carcinoma sensitive APG-115 Preclinical - Cell line xenograft Actionable In a preclinical study, a TP53 wild-type dedifferentiated papillary thyroid carcinoma cell line treated with APG-115 demonstrated decreased cell viability and induction of cell cycle arrest and apoptosis in culture, and tumor growth suppression and tumor regression in xenograft models (PMID: 28498808). 28498808