Harnessing p53 for targeted cancer therapy: new advances and
future directions

J 2025

Harnessing p53 for targeted cancer therapy: new advances and future directions

ANDRYSÍK, Zdeněk a Joaquin M ESPINOSA

Základní údaje

Originální název

Harnessing p53 for targeted cancer therapy: new advances and future directions

Autoři

ANDRYSÍK, Zdeněk a Joaquin M ESPINOSA

Vydání

TRANSCRIPTION-AUSTIN, PHILADELPHIA, TAYLOR & FRANCIS INC, 2025, 2154-1264

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.400 v roce 2024

Označené pro přenos do RIV

Ano

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

p53; nutlin; nelfinavir; integrated stress response; polytherapy; combination therapy

Štítky

14110513, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 25. 2. 2026 14:32, Mgr. Tereza Miškechová

Anotace

V originále

The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.

Návaznosti

GA25-18368S, projekt VaV

Název: Posílení p53 ke spuštění buněčné smrti v nádorech

Investor: Grantová agentura ČR, Posílení p53 ke spuštění buněčné smrti v nádorech

MUNI/11/JRG/0230/2024, interní kód MU

Název: Výzkumná skupina Zdeňka Andrysíka: Molekulární mechanismy rakoviny

Investor: Masarykova univerzita, Výzkumná skupina Zdeňka Andrysíka: Molekulární mechanismy rakoviny, Juniorní výzkumná skupina

Citovat

ANDRYSÍK, Zdeněk a Joaquin M ESPINOSA. Harnessing p53 for targeted cancer therapy: new advances and future directions. TRANSCRIPTION-AUSTIN. PHILADELPHIA: TAYLOR & FRANCIS INC, 2025, roč. 16, č. 1, s. 3-46. ISSN 2154-1264. Dostupné z: https://doi.org/10.1080/21541264.2025.2452711.

@article{2556698,
   author = {Andrysík, Zdeněk and Espinosa, Joaquin M},
   article_location = {PHILADELPHIA},
   article_number = {1},
   doi = {https://doi.org/10.1080/21541264.2025.2452711},
   keywords = {p53; nutlin; nelfinavir; integrated stress response; polytherapy; combination therapy},
   language = {eng},
   issn = {2154-1264},
   journal = {TRANSCRIPTION-AUSTIN},
   title = {Harnessing p53 for targeted cancer therapy: new advances and future directions},
   url = {https://www.tandfonline.com/doi/full/10.1080/21541264.2025.2452711},
   volume = {16},
   year = {2025}
}

TY  - JOUR
ID  - 2556698
AU  - Andrysík, Zdeněk - Espinosa, Joaquin M
PY  - 2025
TI  - Harnessing p53 for targeted cancer therapy: new advances and future directions
JF  - TRANSCRIPTION-AUSTIN
VL  - 16
IS  - 1
SP  - 3-46
EP  - 3-46
PB  - TAYLOR & FRANCIS INC
SN  - 21541264
KW  - p53
KW  - nutlin
KW  - nelfinavir
KW  - integrated stress response
KW  - polytherapy
KW  - combination therapy
UR  - https://www.tandfonline.com/doi/full/10.1080/21541264.2025.2452711
N2  - The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.
ER  -

ANDRYSÍK, Zdeněk a Joaquin M ESPINOSA. Harnessing p53 for targeted cancer therapy: new advances and future directions. \textit{TRANSCRIPTION-AUSTIN}. PHILADELPHIA: TAYLOR \&{} FRANCIS INC, 2025, roč.~16, č.~1, s.~3-46. ISSN~2154-1264. Dostupné z: https://doi.org/10.1080/21541264.2025.2452711.

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