Reference Detail

Ref Type

Journal Article

PMID

(34907344)

Authors

Klimovich B, Merle N, Neumann M, Elmshäuser S, Nist A, Mernberger M, Kazdal D, Stenzinger A, Timofeev O, Stiewe T

Title

p53 partial loss-of-function mutations sensitize to chemotherapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	41	7	2022 Feb	1011-1023	Oncogene

URL

Abstract Text

The tumor suppressive transcription factor p53 is frequently inactivated in cancer cells by missense mutations that cluster in the DNA binding domain. 30% hit mutational hotspot residues, resulting in a complete loss of transcriptional activity and mutant p53-driven chemotherapy resistance. Of the remaining 70% of non-hotspot mutants, many are partial loss-of-function (partial-LOF) mutants with residual transcriptional activity. The therapeutic consequences of a partial-LOF have remained largely elusive. Using a p53 mutation engineered to reduce DNA binding, we demonstrate that partial-LOF is sufficient to enhance oncogene-driven tumorigenesis in mouse models of lung and pancreatic ductal adenocarcinoma and acute myeloid leukemia. Interestingly, mouse and human tumors with partial-LOF mutations showed mutant p53 protein accumulation similar as known for hotspot mutants. Different from the chemotherapy resistance caused by p53-loss, the partial-LOF mutant sensitized to an apoptotic chemotherapy response and led to a survival benefit. Mechanistically, the pro-apoptotic transcriptional activity of mouse and human partial-LOF mutants was rescued at high mutant protein levels, suggesting that accumulation of partial-LOF mutants enables the observed apoptotic chemotherapy response. p53 non-hotspot mutants with partial-LOF, therefore, represent tumorigenic p53 mutations that need to be distinguished from other mutations because of their beneficial impact on survival in a therapy context.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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	R181H	missense	loss of function - predicted	TP53 R181H lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). R181H results in colony growth similar to wild-type Tp53 in cultured cells (PMID: 33257846), but decreased transactivation activity (PMID: 34907344), and therefore, is predicted to lead to a loss of Tp53 protein function.
TP53	R181P	missense	loss of function	TP53 R181P lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). R181P confers a loss of function to the Tp53 protein as demonstrated by a loss of transactivation activity in cell culture (PMID: 23149933, PMID: 34907344).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 E180R	acute myeloid leukemia	sensitive	Cytarabine + Doxorubicin	Preclinical	Actionable	In a preclinical study, the combination of Cytosar-U (cytarabine) and Adriamycin (doxorubicin) inhibited tumor growth and increased survival (p<0.0001) compared to control treatment in a mouse model of acute myeloid leukemia harboring TP53 E177R (corresponding to E180R in human) (PMID: 34907344).	34907344