Reference Detail

Ref Type

Journal Article

PMID

(26294215)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	75	18	2015 Sep 15	3842-52	Cancer Res

URL

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
NSC59984	NSC59984	4	0

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 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 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
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	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 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