24IN - Targeting the DDR – DNA PK inhibition

Date 06 March 2018
Event TAT 2018 - Targeted Anticancer Therapies
Session DNA targets: Damage, repair and immunotherapy
Topics Cytotoxic agents
Presenter Frank Zenke
Citation Annals of Oncology (2018) 29 (suppl_3): iii1-iii6. 10.1093/annonc/mdy046
Authors F.T. Zenke
  • Translational Innovation Platform Oncology, Merck, 64293 - Darmstadt/DE

Abstract

Deoxyribonucleic acid-dependent protein kinase (DNA-PK) plays a critical role in the repair of DNA double strand break (DSBs). DNA double stranded breaks are the most lethal type of DNA lesion, and cells have developed two distinct repair pathways to protect the cell genome from the deleterious effect of DSBs. While homologous recombination occurs mainly during S and G2 phase and requires a homologous DNA template, non-homologous end-joining, (NEJH) uses direct ligation of DNA ends without a homologous DNA template and can therefore take place anytime during the cell cycle.

DNA-PK is a key enzyme in NHEJ-mediated repair of DSBs and, therefore, represents an attractive pharmacological target. Selective inhibition of DNA-PK could synergistically enhance the activity of many commonly used DSB inducing treatment modalities, such as radiotherapy and certain chemotherapeutic agents.

The presentation will provide an overview of the biological role of DNA-PK in normal and cancer cells, available pre-clinical data that explore the effect of DNA-PK inhibition in vitro and in vivo, and early data from DNA-PK inhibitors currently in clinical development.