DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions.

Medova, Michaela; Medo, Matúš; Hovhannisyan, Lusine; Muñoz-Maldonado, Carmen; Aebersold, Daniel M.; Zimmer, Yitzhak (2020). DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions. Pharmacology & therapeutics, 215, p. 107617. Elsevier 10.1016/j.pharmthera.2020.107617

[img]
Preview
Text
1-s2.0-S0163725820301479-main.pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND).

Download (1MB) | Preview

The DNA-PK holoenzyme is a fundamental element of the DNA damage response machinery (DDR), which is responsible for cellular genomic stability. Consequently, and predictably, over the last decades since its identification and characterization, numerous pre-clinical and clinical studies reported observations correlating aberrant DNA-PK status and activity with cancer onset, progression and responses to therapeutic modalities. Notably, various studies have established in recent years the role of DNA-PK outside the DDR network, corroborating its role as a pleiotropic complex involved in transcriptional programs that operate biologic processes as epithelial to mesenchymal transition (EMT), hypoxia, metabolism, nuclear receptors signaling and inflammatory responses. In particular tumor entities as prostate cancer, immense research efforts assisted mapping and describing the overall signaling networks regulated by DNA-PK that control metastasis and tumor progression. Correspondingly, DNA-PK emerges as an obvious therapeutic target in cancer and data pertaining to various pharmacological approaches have been published, largely in context of combination with DNA-damaging agents (DDAs) that act by inflicting DNA double strand breaks (DSBs). Currently, new generation inhibitors are tested in clinical trials. Several excellent reviews have been published in recent years covering the biology of DNA-PK and its role in cancer. In the current article we are aiming to systematically describe the main findings on DNA-PK signaling in major cancer types, focusing on both preclinical and clinical reports and present a detailed current status of the DNA-PK inhibitors repertoire.

Item Type:

Journal Article (Review Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology

UniBE Contributor:

Medova, Michaela; Medo, Matúš; Hovhannisyan, Lusine; Muñoz Maldonado, Carmen; Aebersold, Daniel and Zimmer, Yitzhak

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0163-7258

Publisher:

Elsevier

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

09 Dec 2020 18:21

Last Modified:

13 Dec 2020 02:51

Publisher DOI:

10.1016/j.pharmthera.2020.107617

PubMed ID:

32610116

Uncontrolled Keywords:

Cancer Clinical trials DNA-PK Non-homologous end-joining Targeting

BORIS DOI:

10.7892/boris.148446

URI:

https://boris.unibe.ch/id/eprint/148446

Actions (login required)

Edit item Edit item
Provide Feedback