Key players in the mutant p53 team: small molecules, gene editing, immunotherapy
Key players in the mutant p53 team: small molecules, gene editing, immunotherapy
The transcription factor p53 is a key tumor suppressor that is inactivated in almost all cancers due to either point mutations in the TP53 gene or overexpression of its negative regulators. The p53 protein is known as the “cellular gatekeeper” for its roles in facilitating DNA repair, cell cycle arrest or apoptosis upon DNA damage. Most p53 mutations are missense and result in either structural destabilization of the protein, causing its partial unfolding and deactivation under physiological conditions, or impairment of its DNA-binding properties. Tumor cells with p53 mutations are generally more immunogenic due to “hot spot” neoantigens that instigate the immune system response. In this review, we discuss the key therapeutic strategies targeting mutant p53 tumors, including classical approaches based on small molecule intervention and emerging technologies such as gene editing and T cell immunotherapy.
CRISPR/Cas gene editing, adenoviral gene therapy, immunotherapy, mutation, p53, small molecules
Chasov, Vitaly
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Mirgayazova, Regina
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Zmievskaya, Ekaterina
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Khadiullina, Raniya
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Valiullina, Aygul
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Stephenson Clarke, Joseph Richard
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Rizvanov, Albert
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Baud, Matthias G.J.
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Bulatov, Emil
604a6ecd-d91c-42d2-bb16-0eb720b2b7b3
18 August 2020
Chasov, Vitaly
65364491-ad64-46da-a303-ae6a63abd56e
Mirgayazova, Regina
fbe44855-d5cb-427b-b538-f9d84aa65ed5
Zmievskaya, Ekaterina
5dccac8d-a4c2-4c60-a873-4e1643c3564d
Khadiullina, Raniya
560b02a8-6381-4fb6-b359-5d020e76a675
Valiullina, Aygul
0cda654c-125d-4873-87a3-481c8e4e638f
Stephenson Clarke, Joseph Richard
f92a6e84-4929-4908-a88b-0522b1703916
Rizvanov, Albert
f0ada3be-27b9-4775-a487-defe497a33e9
Baud, Matthias G.J.
8752d519-3d33-43b6-9a77-ab731d410c2e
Bulatov, Emil
604a6ecd-d91c-42d2-bb16-0eb720b2b7b3
Chasov, Vitaly, Mirgayazova, Regina, Zmievskaya, Ekaterina, Khadiullina, Raniya, Valiullina, Aygul, Stephenson Clarke, Joseph Richard, Rizvanov, Albert, Baud, Matthias G.J. and Bulatov, Emil
(2020)
Key players in the mutant p53 team: small molecules, gene editing, immunotherapy.
Frontiers in Oncology, 10, [1460].
(doi:10.3389/fonc.2020.01460).
Abstract
The transcription factor p53 is a key tumor suppressor that is inactivated in almost all cancers due to either point mutations in the TP53 gene or overexpression of its negative regulators. The p53 protein is known as the “cellular gatekeeper” for its roles in facilitating DNA repair, cell cycle arrest or apoptosis upon DNA damage. Most p53 mutations are missense and result in either structural destabilization of the protein, causing its partial unfolding and deactivation under physiological conditions, or impairment of its DNA-binding properties. Tumor cells with p53 mutations are generally more immunogenic due to “hot spot” neoantigens that instigate the immune system response. In this review, we discuss the key therapeutic strategies targeting mutant p53 tumors, including classical approaches based on small molecule intervention and emerging technologies such as gene editing and T cell immunotherapy.
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Accepted/In Press date: 9 July 2020
e-pub ahead of print date: 18 August 2020
Published date: 18 August 2020
Additional Information:
Funding Information:
Funding. Section on small molecule re-activators was funded by RSF grant 19-74-10022 to EB, and by start-up funds from the Southampton School of Chemistry, EPSRC, and Royal Society International Exchanges Cost Share (IEC\R2\181097) funds to MB. Section on gene editing was funded by RFBR grant 19-54-10005 to EB. Work was performed according to the Russian Government Program of Competitive Growth of Kazan Federal University.
Publisher Copyright:
© Copyright © 2020 Chasov, Mirgayazova, Zmievskaya, Khadiullina, Valiullina, Stephenson Clarke, Rizvanov, Baud and Bulatov.
Keywords:
CRISPR/Cas gene editing, adenoviral gene therapy, immunotherapy, mutation, p53, small molecules
Identifiers
Local EPrints ID: 444147
URI: http://eprints.soton.ac.uk/id/eprint/444147
ISSN: 2234-943X
PURE UUID: fc05794f-4d0e-4301-8260-dd59ba0fc07a
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Date deposited: 29 Sep 2020 17:33
Last modified: 17 Mar 2024 03:41
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Contributors
Author:
Vitaly Chasov
Author:
Regina Mirgayazova
Author:
Ekaterina Zmievskaya
Author:
Raniya Khadiullina
Author:
Aygul Valiullina
Author:
Joseph Richard Stephenson Clarke
Author:
Albert Rizvanov
Author:
Emil Bulatov
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