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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 Cancer cell
Vol 34
Issue 2
Date 2018 Aug 13
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 a 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: 21925707, PMID: 25480502, PMID: 30107178), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Feb 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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