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|Ref Type||Journal Article|
|Authors||Zhang S, Zhou L, Hong B, van den Heuvel AP, Prabhu VV, Warfel NA, Kline CL, Dicker DT, Kopelovich L, El-Deiry WS|
|Title||Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53.|
|Date||2015 Sep 15|
|Abstract Text||The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|NSC59984||NSC 59984||p53 Activator 11||NSC59984 is a small molecule that both induces degradation of mutant Tp53 and reactivates Tp53 pathway signaling through Tp73, which may result in increased cell death in Tp53-mutant tumor cells (PMID: 26294215, PMID: 30667081).|
|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 mutant||colorectal cancer||predicted - sensitive||NSC59984||Preclinical - Cell line xenograft||Actionable||In a preclinical study, NSC59984 treatment resulted in increased Tp53 signaling and cell death in colorectal cancer cell lines harboring TP53 mutations, and inhibited tumor growth in TP53-mutant cell line colorectal cancer xenograft models (PMID: 26294215).||26294215|
|TP53 R273H TP53 P309S||colorectal cancer||sensitive||NSC59984||Preclinical - Cell culture||Actionable||In a preclinical study, treatment with NSC59984 induced Tp53 pathway signaling, degradation of mutant Tp53, and cell death in a colorectal cancer cell line harboring TP53 R273H and TP53 P309S in culture (PMID: 26294215).||26294215|
|TP53 R175L||colorectal cancer||sensitive||NSC59984||Preclinical - Cell culture||Actionable||In a preclinical study, treatment with NSC59984 resulted in increased degradation of mutant Tp53 and cell death in a colorectal cancer cell line harboring TP53 R175L in culture (PMID: 26294215).||26294215|
|TP53 R273H TP53 P309S||colorectal cancer||sensitive||Cisplatin + NSC59984||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of Platinol (cisplatin) and NSC59984 worked synergistically to decrease viability of a colorectal cancer cell line harboring TP53 R273H and TP53 P309S in culture (PMID: 26294215).||26294215|
|TP53 R175H||colorectal cancer||sensitive||NSC59984||Preclinical - Cell culture||Actionable||In a preclinical study, treatment with NSC59984 resulted in increased degradation of mutant Tp53 and cell death in a colorectal cancer cell line harboring TP53 R175H in culture (PMID: 26294215).||26294215|