Reference Detail

Ref Type

Journal Article

PMID

(21643018)

Authors

Aziz MH, Shen H, Maki CG

Title

Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	30	46	2011 Nov 17	4678-86	Oncogene

URL

Abstract Text

Wild-type p53 is a stress-responsive tumor suppressor and potent growth inhibitor. Genotoxic stresses (for example, ionizing and ultraviolet radiation or chemotherapeutic drug treatment) can activate p53, but also induce mutations in the P53 gene, and thus select for p53-mutated cells. Nutlin-3a (Nutlin) is pre-clinical drug that activates p53 in a non-genotoxic manner. Nutlin occupies the p53-binding pocket of murine double minute 2 (MDM2), activating p53 by blocking the p53-MDM2 interaction. Because Nutlin neither binds p53 directly nor introduces DNA damage, we hypothesized Nutlin would not induce P53 mutations, and, therefore, not select for p53-mutated cells. To test this, populations of SJSA-1 (p53 wild-type) cancer cells were expanded that survived repeated Nutlin exposures, and individual clones were isolated. Group 1 clones were resistant to Nutlin-induced apoptosis, but still underwent growth arrest. Surprisingly, while some Group 1 clones retained wild-type p53, others acquired a heterozygous p53 mutation. Apoptosis resistance in Group 1 clones was associated with decreased PUMA induction and decreased caspase 3/7 activation. Group 2 clones were resistant to both apoptosis and growth arrest induced by Nutlin. Group 2 clones had acquired mutations in the p53-DNA-binding domain and expressed only mutant p53s that were induced by Nutlin treatment, but were unable to bind the P21 and PUMA gene promoters, and unable to activate transcription. These results demonstrate that non-genotoxic p53 activation (for example, by Nutlin treatment) can lead to the acquisition of somatic mutations in p53 and select for p53-mutated cells. These findings have implications for the potential clinical use of Nutlin and other small molecule MDM2 antagonists.

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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
TP53	E258Q	missense	loss of function	TP53 E258Q lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). E258Q confers a loss of Tp53 DNA binding ability and transcriptional activation in cell culture (PMID: 21643018).
TP53	I232S	missense	loss of function	TP53 I232S lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). I232S results in a loss of Tp53 DNA-binding ability and transcriptional activity in cell culture (PMID: 21643018).
TP53	P177T	missense	loss of function	TP53 P177T lies within the DNA binding domain of the Tp53 protein (UniProt.org). P177T results in a loss of Tp53 function as indicated by inability to bind DNA or activate transcription in cell culture (PMID: 21643018).
TP53	R280M	missense	loss of function	TP53 R280M lies within the DNA binding domain of the Tp53 protein (UniProt.org). R280M results in decreased DNA binding and activation of Tp53 target genes and resistance to apoptosis in cell culture (PMID: 21643018).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 R280M	osteosarcoma	resistant	Nutlin-3a	Preclinical	Actionable	In a preclinical study, TP53 R280M resulted in secondary resistance in an osteosarcoma cell line acquired during Nutlin-3 treatment (PMID: 21643018).	21643018
TP53 P177T	osteosarcoma	resistant	Nutlin-3a	Preclinical	Actionable	In a preclinical study, TP53 P177T resulted in secondary resistance in an osteosarcoma cell line acquired during Nutlin-3 treatment (PMID: 21643018).	21643018
TP53 E258Q	osteosarcoma	resistant	Nutlin-3a	Preclinical	Actionable	In a preclinical study, TP53 E258Q resulted in secondary resistance in an osteosarcoma cell line acquired during Nutlin-3 treatment (PMID: 21643018).	21643018
TP53 I232S	osteosarcoma	resistant	Nutlin-3a	Preclinical	Actionable	In a preclinical study, TP53 I232S resulted in secondary resistance in an osteosarcoma cell line acquired during Nutlin-3 treatment (PMID: 21643018).	21643018