Reference Detail

Ref Type

Journal Article

PMID

(31483066)

Authors

Timofeev O, Klimovich B, Schneikert J, Wanzel M, Pavlakis E, Noll J, Mutlu S, Elmshäuser S, Nist A, Mernberger M, Lamp B, Wenig U, Brobeil A, Gattenlöhner S, Köhler K, Stiewe T

Title

Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The EMBO journal	38	20	2019 10 15	e102096	EMBO J

URL

Abstract Text

Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53R178E mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53-/- mice. Surprisingly, stabilization of p53R178E in Mdm2-/- mice nevertheless triggers extensive apoptosis, indicative of residual wild-type activities. Although this apoptotic activity suffices to trigger lethality of Trp53R178E ;Mdm2-/- embryos, it proves insufficient for suppression of spontaneous and oncogene-driven tumorigenesis. Trp53R178E mice develop tumors indistinguishably from Trp53-/- mice and tumors retain and even stabilize the p53R178E protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53R178E tumors exhibit remarkably better chemotherapy responses than Trp53-/- ones, resulting in enhanced eradication of p53-mutated tumor cells. Together, this provides genetic proof-of-principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy.

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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
TP53	R181E	missense	loss of function	TP53 R181E lies within the DNA-binding domain of the Tp53 protein (PMID: 21760703). R181E results in a loss of DNA binding ability and activation of downstream targets, increased accumulation of Tp53, and fails to induce apoptosis and inhibit proliferation in culture, and induces tumor formation in animal models (PMID: 31483066).
TP53	R181L	missense	loss of function	TP53 R181L lies within the DNA-binding domain of the Tp53 protein (PMID: 21760703). R181L results in cell cycle arrest similar to wild-type Tp53, however, leads to a selective loss of DNA binding and activation of a downstream promoter, IGF-BP3 box B, and fails to induce apoptosis in culture (PMID: 31483066, PMID: 20471942, PMID: 8756654).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 R181E	Advanced Solid Tumor	no benefit	Nutlin-3a	Preclinical - Cell culture	Actionable	In a preclinical study, Nutlin-3 treatment did not reduce cell proliferation and viability in transformed mouse cells expressing TP53 R181E in culture (PMID: 31483066).	31483066
TP53 R181E	Advanced Solid Tumor	sensitive	Doxorubicin + RG7112	Preclinical - Cell culture	Actionable	In a preclinical study, RG7112 (RO5045337) and Adriamycin (doxorubicin) combination treatment induced cytotoxicity in transformed mouse cells expressing TP53 R181E in culture (PMID: 31483066).	31483066
TP53 R181E	Advanced Solid Tumor	sensitive	Doxorubicin + Nutlin-3a	Preclinical - Cell culture	Actionable	In a preclinical study, Nutlin-3 and Adriamycin (doxorubicin) combination treatment inhibited proliferation and viability of transformed mouse cells expressing TP53 R181E in culture (PMID: 31483066).	31483066
TP53 R181E	lung adenocarcinoma	sensitive	Doxorubicin + Nutlin-3a	Preclinical - Cell culture	Actionable	In a preclinical study, a lung adenocarcinoma cell line expressing TP53 R181E demonstrated enhanced sensitivity to Adriamycin (doxorubicin) treatment when combined with Nutlin-3, and induced apoptosis in culture (PMID: 31483066).	31483066
TP53 R175P	lung adenocarcinoma	no benefit	Doxorubicin + Nutlin-3a	Preclinical - Cell culture	Actionable	In a preclinical study, Nutlin-3 and Adriamycin (doxorubicin) combination treatment did not induce apoptosis in a lung adenocarcinoma cell line expressing TP53 R175P in culture (PMID: 31483066).	31483066
TP53 R181E	Advanced Solid Tumor	sensitive	Doxorubicin + Idasanutlin	Preclinical - Cell culture	Actionable	In a preclinical study, Idasanutlin (RG7388) and Adriamycin (doxorubicin) combination treatment induced cytotoxicity in transformed mouse cells expressing TP53 R181E in culture (PMID: 31483066).	31483066
TP53 R181E	Advanced Solid Tumor	sensitive	Doxorubicin + SAR405838	Preclinical - Cell culture	Actionable	In a preclinical study, SAR405838 and Adriamycin (doxorubicin) combination treatment induced cytotoxicity in transformed mouse cells expressing TP53 R181E in culture (PMID: 31483066).	31483066
TP53 R181L	lung adenocarcinoma	sensitive	Doxorubicin + Nutlin-3a	Preclinical - Cell culture	Actionable	In a preclinical study, a lung adenocarcinoma cell line expressing TP53 R181L demonstrated enhanced sensitivity to Adriamycin (doxorubicin) treatment when combined with Nutlin-3, and induced apoptosis in culture (PMID: 31483066).	31483066