Reference Detail

Ref Type

Journal Article

PMID

(30107178)

Authors

Schulz-Heddergott R, Stark N, Edmunds SJ, Li J, Conradi LC, Bohnenberger H, Ceteci F, Greten FR, Dobbelstein M, Moll UM

Title

Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	34	2	2018 Aug 13	298-314.e7	Cancer Cell

URL

Abstract Text

Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53R248Q/W are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.

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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	R248Q	missense	loss of function	TP53 R248Q is a hotspot mutation that lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). R248Q results in increased proliferation, migration, invasion, and protein stability and altered subcellular localization in culture (PMID: 37030635), loss of DNA binding and decreased transactivation of Tp53 targets and interference with wild-type Tp53 transactivation, leads to resistance to apoptosis and failure of G1 arrest in cell culture (PMID: 23538418, PMID: 16861262, PMID: 31395785), as well as increased Akt activation, Stat3 dependent migration, and enhanced tumor onset and growth in mouse models (PMID: 30107178).
TP53	T170M	missense	unknown	TP53 T170M lies within the DNA-binding domain of the Tp53 protein (PMID: 21760703). T170M has been identified in the scientific literature (PMID: 36979829, PMID: 37185420, PMID: 30107178), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Sep 2023).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 R248Q	colorectal cancer	predicted - sensitive	Napabucasin	Preclinical - Cell culture	Actionable	In a preclinical study, Napabucasin (BBI608) treatment reduced Stat3 phosphorylation and impaired wound healing in colorectal cancer cell lines expressing TP53 R248Q in culture (PMID: 30107178).	30107178
TP53 del	colorectal cancer	decreased response	Tanespimycin	Preclinical	Actionable	In a preclincal study, Tanespimycin (17-AAG) treatment of mutagen induced colorectal cancer in a genetic mouse model with biallelic loss of TP53 was less effective than treatment of mice bearing a single allele with a TP53 R248Q mutation (PMID: 30107178).	30107178
TP53 R248Q	colorectal cancer	sensitive	Tanespimycin	Preclinical	Actionable	In a preclincal study, Tanespimycin (17-AAG) treatment reduced p-Stat3 expression, induced apoptosis, and inhibited tumor growth of mutagen induced colorectal cancer in a genetic mouse model expressing TP53 R248Q (PMID: 30107178).	30107178