DNA DAMAGE RESPONSE

The DNA-PK pathway

One of the major pathways of double-strand breaks (DSB) repair is non-homologous end joining (NHEJ). DNA-dependent protein kinase (DNA‑PK) is thought to be induced by exposure to cancer therapeutics. DNA‑PK is integral to DSB repair; this contributes to the survival of cancer cells exposed to double-stranded break-inducing therapies.1-3

Replication stress results in DSBs in DNA which is recognized by DNA‑PKcs. DNA‑PKcs subsequently binds to Ku to form the DNA‑PK complex. Other factors are recruited to form the NHEJ complex at the double-strand break. DNA‑PK phosphorylation induces a conformational change in NHEJ, which enables DNA repair.2-4

Peposertib (DNA‑PK inhibitor)

Description and Mechanism of Action:

Peposertib is an investigational small-molecule inhibitor of DNA‑PK. DNA‑PK is a key enzyme for NHEJ, an important DNA DSB repair pathway. DNA‑PK inhibition impairs NHEJ repair, leading to persistent DNA double-strand breaks and subsequent tumor cell death.5,6

Peposertib (formerly M3814) is an investigational orally administered, small-molecule, selective DNA‑PK inhibitor designed to block DNA‑PK activity. This inhibits its ability to function in the DNA repair process leading to the persistence of DNA DSBs and subsequent cell death.5

The DNA-PK Pathway

Areas of interest:

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Abbreviations:
ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia RAD3-related; DNA-PKcs, DNA-dependent protein kinase catalytic subunit.

References:

  1. Scully R, Panday A, Elango R, Willis NA. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat Rev Mol Cell Biol. 2019;20(11):698-714.
  2. Davis AJ, Chen DJ. DNA double strand break repair via non-homologous end-joining. Transl Cancer Res. 2013;2(3):130-143.
  3. Davis AJ, Chen BPC, Chen DJ. DNA-PK: a dynamic enzyme in a versatile DSB repair pathway. DNA Repair (Amst). 2014;17:21-29.
  4. Brown JS, O'Carrigan B, Jackson SP, Yap TA. Targeting DNA repair in cancer: beyond PARP inhibitors. Cancer Discov. 2017;7(1):20-37.
  5. van Bussel MTJ, Awada A, de Jonge MJA, et al. A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours. Br J Cancer. 2021;124(4):728-735.
  6. Zenke FT, Zimmermann A, Sirrenberg C, et al. Pharmacologic inhibitor of DNA-PK, M3814, potentiates radiotherapy and regresses human tumors in mouse models. Mol Cancer Ther. 2020;19(5):1091-1101.
  7. Testing the combination of new anti-cancer drug peposertib with avelumab and radiation therapy for advanced/metastatic solid tumors. ClinicalTrials.gov identifier: NCT04068194. Updated November 4, 2021. Accessed November 4, 2021. https://clinicaltrials.gov/ct2/show/NCT04068194
  8. Study of avelumab-M3814 combinations. ClinicalTrials.gov identifier: NCT03724890. Updated August 17, 2021. Accessed November 4, 2021. https://clinicaltrials.gov/ct2/show/NCT03724890

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