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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
The Enigmatic Tumor Suppressor p53 Biomolecule: Its Role and Prognostic and Predictive Values in Cancer Therapy and
1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77096, USA.
Abstract:
The p53 biomolecule is critical for facile antitumor response in cancer therapy. Once fully activated, p53 will kill tumor cells by activating programmed cell death (PCD), such as apoptosis and ferroptosis, and inducing immunogenic cell death. It is not surprising, therefore, that in about 50% of cancers p53 is mutated and non-functional, which induces drug resistance. Paradoxically, many cancers harboring the wild-type p53 genotype also become resistant via loss of drug-induced activation of p53. Efforts to convert loss-of-function or gain-of-function mutant p53 to the wild-type phenotype or to activate wild-type p53 through drug design have been disappointing. There is also a failure to recognize the existence of a sizeable number of mutant p53s that are phenotypically normal but cannot be functionally activated. Since such mutants and wild-type p53 retain intrinsic PCD pathways, focus on activating p53 could be more rewarding if the efforts implemented recognize and incorporate mechanistic factors that are vital for activating p53 function. This would realize a seminal goal of harnessing the true potential of p53 through more rational and effective therapeutic strategies and finally fulfill a critical unmet clinical need, particularly in the context of precision medicine. For such a vision, functional evaluation of normal (wild-type) or mutant p53 (or FENOMP) is vital and, thus, proposed herein as a conceptual assay to predict the phenotype of p53.
Insights
Activating the p53 protein is key to cancer therapy, but mutations and resistance mechanisms hinder its function. A new conceptual assay is proposed to evaluate p53 function for improved cancer treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The p53 biomolecule plays a crucial role in initiating antitumor responses through programmed cell death (PCD) pathways like apoptosis and ferroptosis.
- Approximately 50% of cancers feature mutated, non-functional p53, leading to drug resistance. Paradoxically, wild-type p53 can also lose function in resistant cancers.
- Current therapeutic strategies targeting p53 dysfunction, including converting mutants to wild-type or activating wild-type p53, have yielded disappointing results.
Purpose of the Study:
- To address the challenge of p53 dysfunction in cancer therapy by proposing a novel conceptual assay for functional evaluation.
- To highlight the need to recognize and incorporate mechanistic factors crucial for p53 activation in therapeutic strategies.
- To facilitate the harnessing of p53's full potential for more rational and effective cancer treatments, particularly within precision medicine.
Main Methods:
- The study proposes a conceptual assay for the functional evaluation of both normal (wild-type) and mutant p53.
- This assay aims to predict the phenotype of p53, distinguishing between functional and non-functional variants.
- The approach considers the intrinsic PCD pathways retained by both wild-type and certain mutant p53 forms.
Main Results:
- The research identifies a significant number of mutant p53 proteins that are phenotypically normal but functionally inactive.
- It emphasizes that both wild-type and functionally compromised p53 variants retain intrinsic programmed cell death pathways.
- The proposed assay offers a method to predict p53 phenotype, crucial for understanding drug resistance.
Conclusions:
- Activating p53 function, by understanding its mechanistic requirements, holds significant promise for advancing cancer therapy.
- A functional evaluation assay for p53 is vital for developing effective therapeutic strategies and addressing unmet clinical needs in precision oncology.
- Harnessing the full potential of p53 requires a deeper understanding of its functional activation mechanisms, moving beyond simple genotype considerations.
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