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Ref Type Journal Article
PMID (22438244)
Authors Jemaa M, Vitale I, Kepp O, Berardinelli F, Galluzzi L, Senovilla L, Marino G, Malik SA, Rello-Varona S, Lissa D, Antoccia A, Tailler M, Schlemmer F, Harper F, Pierron G, Castedo M, Kroemer G
Title Selective killing of p53-deficient cancer cells by SP600125.
Journal Vol Issue Date Pages Journal Short Title
EMBO molecular medicine 4 6 2012 Jun 500-14 EMBO Mol Med
URL
Abstract Text The genetic or functional inactivation of p53 is highly prevalent in human cancers. Using high-content videomicroscopy based on fluorescent TP53(+/+) and TP53(-/-) human colon carcinoma cells, we discovered that SP600125, a broad-spectrum serine/threonine kinase inhibitor, kills p53-deficient cells more efficiently than their p53-proficient counterparts, in vitro. Similar observations were obtained in vivo, in mice carrying p53-deficient and -proficient human xenografts. Such a preferential cytotoxicity could be attributed to the failure of p53-deficient cells to undergo cell cycle arrest in response to SP600125. TP53(-/-) (but not TP53(+/+) ) cells treated with SP600125 became polyploid upon mitotic abortion and progressively succumbed to mitochondrial apoptosis. The expression of an SP600125-resistant variant of the mitotic kinase MPS1 in TP53(-/-) cells reduced SP600125-induced polyploidization. Thus, by targeting MPS1, SP600125 triggers a polyploidization program that cannot be sustained by TP53(-/-) cells, resulting in the activation of mitotic catastrophe, an oncosuppressive mechanism for the eradication of mitosis-incompetent cells.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 loss colon carcinoma sensitive SP600125 Preclinical Actionable In a preclinical study, SP600125 induced cell death in colon carcinoma cells deficient for p53 (PMID: 22438244). 22438244