p53 partial loss-of-function mutations sensitize to chemotherapy

Klimovich, Boris; Merle, Nastasja; Neumann, Michelle; Elmshäuser, Sabrina; Nist, Andrea; Mernberger, Marco; Kazdal, Daniel; Timofeev, Oleg; Stiewe, Thorsten

doi:10.1038/s41388-021-02141-5

Cited by 30 publications

(18 citation statements)

References 56 publications

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“…Most common p53 missense mutations, including all hotspots have a complete or partial loss of WT function [ 63 , 64 ]. Many mutants exist in a distorted conformation that prevents them from binding to the DNA and exert p53 function.…”

Section: Strategies That Exploit Mutant P53 Expressionmentioning

confidence: 99%

GOF Mutant p53 in Cancers: A Therapeutic Challenge

Dolma

Müller

2022

Cancers

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TP53 is mutated in the majority of human cancers. Mutations can lead to loss of p53 expression or expression of mutant versions of the p53 protein. These mutant p53 proteins have oncogenic potential. They can inhibit any remaining WTp53 in a dominant negative manner, or they can acquire new functions that promote tumour growth, invasion, metastasis and chemoresistance. In this review we explore some of the mechanisms that make mutant p53 cells resistant to chemotherapy. As mutant p53 tumours are resistant to many traditional chemotherapies, many have sought to explore new ways of targeting mutant p53 tumours and reinstate chemosensitivity. These approaches include targeting of mutant p53 stability, mutant p53 binding partners and downstream pathways, p53 vaccines, restoration of WTp53 function, and WTp53 gene delivery. The current advances and challenges of these strategies are discussed.

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Section: Strategies That Exploit Mutant P53 Expressionmentioning

confidence: 99%

GOF Mutant p53 in Cancers: A Therapeutic Challenge

Dolma

Müller

2022

Cancers

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“…In small cell lung cancer cell lines, the representative cell lines with five mutations (R248Q, R273H, R175H, G245S, or R249S) were found to be more ferroptosis-sensitive than a wild-type TP53 cell line ( 46 , 50 ). The genetic mutation may cause p53 to lose tumor-inhibiting activity of the wild-type protein (LOF, loss of function) or gain new properties (also known as functional gain, GOF) ( 51 ). Nonsense mutation, frameshift mutation or homozygous deletion may cause the function of p53 to be lost ( 52 ).…”

Section: Tp53 Mutation and Pcdmentioning

confidence: 99%

Current insights into the regulation of programmed cell death by TP53 mutation in cancer

Sai

Zhou

et al. 2022

Front. Oncol.

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Gene mutation is a complicated process that influences the onset and progression of cancer, and the most prevalent mutation involves the TP53 gene. One of the ways in which the body maintains homeostasis is programmed cell death, which includes apoptosis, autophagic cell death, pyroptosis, ferroptosis, NETosis, and the more recently identified process of cuprotosis. Evasion of these cell deaths is a hallmark of cancer cells, and our elucidation of the way these cells die helps us better understands the mechanisms by which cancer arises and provides us with more ways to treat it.Studies have shown that programmed cell death requires wild-type p53 protein and that mutations of TP53 can affect these modes of programmed cell death. For example, mutant p53 promotes iron-dependent cell death in ferroptosis and inhibits apoptotic and autophagic cell death. It is clear that TP53 mutations act on more than one pathway to death, and these pathways to death do not operate in isolation. They interact with each other and together determine cell death. This review focuses on the mechanisms via which TP53 mutation affects programmed cell death. Clinical investigations of TP53 mutation and the potential for targeted pharmacological agents that can be used to treat cancer are discussed.

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“…p53 is located on chromosome 17 and its encoded protein serves as a tumor suppressor for protecting the integrity of the genome of cells. This tumor suppressor is often inactivated or mutated in about 70% of pancreatic cancer and most of mutations are the missense mutations, especially at the locus of R248, R273 or R175 [ 34 ]. Using animal models, studies demonstrate that the loss of heterozygosity (LOH) of p53 is an important factor for driving pancreatic cancer progression [ 35 , 36 ].…”

Section: Pancreatic Cancer Etiology and Progressionmentioning

confidence: 99%

A comprehensive review of pancreatic cancer and its therapeutic challenges

Jiang

Fagman

et al. 2022

Aging

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Pancreatic cancer is a devastating and lethal human malignancy with no curable chemo-treatments available thus far. More than 90% of pancreatic tumors are formed from ductal epithelium as pancreatic ductal adenocarcinoma (PDAC), which often accompany with the expression of mutant K-ras. The incidences of pancreatic cancer are expected to increase rapidly worldwide in the near future, due to environmental pollution, obesity epidemics and etc. The dismal prognosis of this malignancy is contributed to its susceptibility to tumor micro-metastasis from inception and the lack of methods to detect precursor lesions at very early stages of the onset until clinical symptoms occur. In recent years, basic and clinical studies have been making promising progresses for discovering markers to determine the subtypes or stages of this malignancy, which allow effectively implementing personalized therapeutic interventions. The purpose of this review is to discuss the existing knowledge of the molecular mechanisms of pancreatic cancer and the current state of treatment options with the emphasis on targeting therapeutic approaches. The specific focuses are on the molecular mechanisms of the disease, identifications of drug resistance, establishment of immune escaping mechanisms as well as potential of targeting identified pathways in combinations with existing chemo-drugs.www.aging-us.com AGINGpancreatic cancer risk and onset. The majority of the incidences of pancreatic cancer occur sporadically and the disease is often accompanied with genetic abnormalities in somatic cells. Studies have indicated that unlike familial cancer syndromes for gastrointestine/colon or breast, pancreatic cancer has very low penetrance with less than 10% of the cases to be linked to a familial setting [3,4]. Among many genetic lesions detected in pancreatic cancer, active mutant K-ras is one that occurs in early stages of pancreatic tumorigenesis, followed by inactivation of several tumor suppressors, including p53, p16 INK4a , and others (such as SMAD4/DPC4, MLH1, LKB1, PRSS1, and BRCA2) [3,4].

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p53 partial loss-of-function mutations sensitize to chemotherapy

Cited by 30 publications

References 56 publications

GOF Mutant p53 in Cancers: A Therapeutic Challenge

GOF Mutant p53 in Cancers: A Therapeutic Challenge

Current insights into the regulation of programmed cell death by TP53 mutation in cancer

A comprehensive review of pancreatic cancer and its therapeutic challenges

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