This article is highlighted in the In This Issue feature, p. Further study is warranted in this patient population. Oral BAY 1895344 was tolerable, with antitumor activity in heavily pretreated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein pharmacodynamic results supported a mechanism of action of increased DNA damage. An expansion phase continues in patients with DDR deficiency. Overall, BAY 1895344 is well tolerated, with antitumor activity against cancers with certain DDR defects, including ATM loss. Responders had ATM protein loss and/or deleterious ATM mutations and received doses ≥40 mg twice daily. Median duration of response was 315.5 days. Partial responses were achieved in 4 patients and stable disease in 8 patients. Most common adverse events were manageable and reversible hematologic toxicities. The MTD was 40 mg twice daily 3 days on/4 days off. We report the dose-escalation portion of the phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5 to 80 mg twice daily in 21 patients with advanced solid tumors. Our findings indicate that DNA-PK recognizes DSBs regardless of chemical complexity but cannot recognize the protein-linked DSBs produced by etoposide and topoisomerase II.Targeting the ataxia telangiectasia and RAD3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. In contrast, the protein-linked DSBs produced by etoposide and topoisomerase II failed to bind and activate DNA-PK. The data indicate that DSBs produced by bleomycin, calicheamicin and two types of ionizing radiation ( 137 Cs γ rays and $$ ions: high and low linear energy transfer, respectively) activate DNA-PK to levels matching the kinase activation obtained with simple restriction endonuclease-induced DSBs. The DNA breaks were tested for the ability to activate purified DNA-PK. To determine whether DNA-PK could recognize DNA strand breaks generated by agents used in the treatment of cancer, we damaged plasmid DNA with anticancer drugs and ionizing radiation. These nucleotides are often damaged when DSBs are introduced by anticancer agents and could therefore prevent recognition by DNA-PK.

We have previously shown that PRKDC is activated when the enzyme interacts with the terminal nucleotides of a DSB. DNA-PK is composed of a DNA-binding subunit, Ku, and a catalytic subunit, DNA-PKcs (PRKDC). The DNA-dependent protein kinase (DNA-PK) is a DNA-end activated protein kinase that is required for efficient repair of DNA double-strand breaks (DSBs) and for normal resistance to ionizing radiation.

36 strand dna activation