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|Ref Type||Journal Article|
|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.|
|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.|
|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: 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||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|
|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|