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Ref Type Journal Article
PMID (23653682)
Authors Wei SJ, Joseph T, Sim AY, Yurlova L, Zolghadr K, Lane D, Verma C, Ghadessy F
Title In vitro selection of mutant HDM2 resistant to Nutlin inhibition.
Journal Vol Issue Date Pages Journal Short Title
PloS one 8 4 2013 e62564 PLoS One
URL
Abstract Text HDM2 binds to the p53 tumour suppressor and targets it for proteosomal degradation. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2 and abrogates its repressive function. Using a novel in vitro selection methodology, we simulated the emergence of resistance by evolving HDM2 mutants capable of binding p53 in the presence of Nutlin concentrations that inhibit the wild-type HDM2-p53 interaction. The in vitro phenotypes were recapitulated in ex vivo assays measuring both p53 transactivation function and the direct p53-HDM2 interaction in the presence of Nutlin. Mutations conferring drug resistance were not confined to the N-terminal p53/Nutlin-binding domain, and were additionally seen in the acidic, zinc finger and RING domains. Mechanistic insights gleaned from this broad spectrum of mutations will aid in future drug design and further our understanding of the complex p53-HDM2 interaction.

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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
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
MDM2 C308Y missense loss of function - predicted MDM2 C308Y lies within the RanBP2-type zinc finger domain of the Mdm2 protein (UniProt.org). C308Y results in decreased Tp53 degradation (PMID: 17116689) and has been shown to confer MDM2 inhibitor resistance in cell culture (PMID: 23653682), and therefore, is predicted to lead to a loss of Mdm2 protein function. Y
MDM2 L82P missense unknown MDM2 L82P lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). L82P has been associated with MDM2 inhibitor resistance in cell culture (PMID: 23653682), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Nov 2023). Y
MDM2 M62A missense unknown MDM2 M62A lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). M62A has been shown to confer MDM2 inhibitor resistance in cell culture (PMID: 23653682, PMID: 25115702, PMID: 24278380), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Nov 2023). Y
MDM2 M62V missense unknown MDM2 M62V lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). M62V has been shown to confer MDM2 inhibitor resistance in cell culture (PMID: 23653682), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Nov 2023). Y
MDM2 P20L missense unknown MDM2 P20L lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). P20L has been shown to confer moderate MDM2 inhibitor resistance in cell culture (PMID: 23653682, PMID: 24278380), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Nov 2023). Y
MDM2 Q24R missense unknown MDM2 Q24R lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). Q24R has been shown to confer MDM2 inhibitor resistance in culture (PMID: 23653682, PMID: 24278380), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Nov 2023). Y
MDM2 T16A missense unknown MDM2 T16A lies within a region of the Mdm2 protein necessary for interaction with USP2 (UniProt.org). T16A has been shown to confer moderate MDM2 inhibitor resistance in cell culture (PMID: 23653682), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Nov 2023). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MDM2 M62A Advanced Solid Tumor predicted - resistant Nutlin-3a Preclinical - Biochemical Actionable In a preclinical study, MDM2 M62A conferred resistance to Nutlin-3a as demonstrated by decreased restoration of Tp53 activity in reporter assays in culture, and impaired inhibition of Mdm2-Tp53 interaction in in vitro assays (PMID: 23653682). 23653682
MDM2 L82P Advanced Solid Tumor predicted - resistant Nutlin-3a Preclinical - Biochemical Actionable In a preclinical study, MDM2 L82P conferred resistance to Nutlin-3a as demonstrated by decreased restoration of Tp53 activity in reporter assays in culture, and impaired inhibition of Mdm2-Tp53 interaction in in vitro assays (PMID: 23653682). 23653682
MDM2 Q24R Advanced Solid Tumor predicted - resistant Nutlin-3a Preclinical - Biochemical Actionable In a preclinical study, MDM2 Q24R conferred moderate resistance to Nutlin-3a as demonstrated by decreased restoration of Tp53 activity in reporter assays in culture, and impaired inhibition of Mdm2-Tp53 interaction in in vitro assays (PMID: 23653682). 23653682
MDM2 M62V Advanced Solid Tumor predicted - resistant Nutlin-3a Preclinical - Biochemical Actionable In a preclinical study, MDM2 M62V conferred partial resistance to Nutlin-3a as demonstrated by decreased restoration of Tp53 activity in reporter assays in culture, and impaired inhibition of Mdm2-Tp53 interaction in in vitro assays (PMID: 23653682). 23653682
MDM2 T16A Advanced Solid Tumor predicted - resistant Nutlin-3a Preclinical - Biochemical Actionable In a preclinical study, MDM2 T16A conferred moderate resistance to Nutlin-3a as demonstrated by decreased restoration of Tp53 activity in reporter assays in culture, and impaired inhibition of Mdm2-Tp53 interaction in in vitro assays (PMID: 23653682). 23653682
MDM2 C308Y Advanced Solid Tumor predicted - resistant Nutlin-3a Preclinical - Biochemical Actionable In a preclinical study, MDM2 C308Y conferred moderate resistance to Nutlin-3a as demonstrated by decreased restoration of Tp53 activity in reporter assays in culture (PMID: 23653682). 23653682
MDM2 P20L Advanced Solid Tumor predicted - resistant Nutlin-3a Preclinical - Biochemical Actionable In a preclinical study, MDM2 P20L conferred moderate resistance to Nutlin-3a as demonstrated by decreased restoration of Tp53 activity in reporter assays in culture, and impaired inhibition of Mdm2-Tp53 interaction in in vitro assays (PMID: 23653682). 23653682