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Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy
Min Lu1, Paul Miller1, Xin Lu1
1Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
Abstract:
The tumour suppressor p53 is a master sensor of stress and it controls the expression of hundreds to thousands of genes with diverse biological functions including cell cycle arrest, apoptosis, and senescence. Consequently p53 is the most mutated gene found in human cancer and p53 mutation rate varies from 5% to 95%. Importantly p53 activity is often inactivated in tumours expressing structurally wild type p53. Thus one of the major challenges in cancer research is to restore the tumour suppressive function of p53. Intensive studies in the past decade have demonstrated that in addition to mutation, p53 activities are largely regulated by cellular factors that control the expression level and/or transcriptional activities of p53. MDM2, MDM4, p14(ARF) and the ASPP family of proteins are among the most studied regulators of p53. With increased understanding of the complexity of p53 regulation, various p53 reactivating approaches are being developed. This review will focus on the recent understanding of p53 inactivation in melanoma and the approaches to reactivate p53 in preclinical studies. Recent success in the therapeutic targeting of the BRAFV600E oncogenic protein was accompanied with subsequent relapse caused by acquired drug resistance. Restoration of the tumour suppressive function of p53 presents a parallel cancer therapeutic opportunity alongside BRAFV600E inhibition. Thus targeted therapy and concurrent reactivation of p53 may be a fertile ground to achieve synergistic killing of the 50% of cancer cells that express structurally wild type p53.
Insights
The tumor suppressor p53 is crucial for cancer prevention but is often inactivated. Reactivating p53 offers a promising therapeutic strategy, especially in melanoma, alongside existing treatments.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The tumor suppressor p53 is a key stress sensor regulating genes involved in cell cycle arrest, apoptosis, and senescence.
- p53 is the most frequently mutated gene in human cancers, with mutation rates ranging from 5% to 95%.
- p53 activity can also be inactivated in tumors with wild-type p53 through regulatory mechanisms.
Purpose of the Study:
- To review recent advances in understanding p53 inactivation in melanoma.
- To explore preclinical approaches for reactivating p53 in cancer therapy.
- To highlight p53 reactivation as a complementary strategy to targeted therapies like BRAFV600E inhibition.
Main Methods:
- Review of existing literature on p53 regulation and inactivation.
- Analysis of preclinical studies investigating p53 reactivation strategies.
- Discussion of the interplay between p53 status and targeted cancer therapies.
Main Results:
- p53 activity is modulated by various cellular factors, including MDM2, MDM4, p14ARF, and ASPP proteins.
- Targeting BRAFV600E in melanoma can lead to drug resistance, underscoring the need for alternative therapeutic avenues.
- Restoring p53 function presents a significant opportunity for synergistic effects when combined with targeted therapies.
Conclusions:
- Reactivating the tumor-suppressive function of p53 is a critical challenge and a promising therapeutic avenue in cancer research.
- Concurrent reactivation of p53 with targeted therapies may overcome drug resistance and enhance treatment efficacy.
- This approach holds potential for synergistic cancer cell killing, particularly in tumors with wild-type p53.