Abstract IA24: Targeting Chk1

The majority of traditional anticancer drugs inhibit DNA synthesis either by directly damaging DNA or by inhibiting synthesis of deoxyribonucleotide precursors. DNA damage induces cell cycle arrest through activation of cell cycle checkpoints whose goal is to prevent further DNA synthesis or mitosis until the damage is repaired. These checkpoints have undergone intense investigation as potential therapeutic targets, and Chk1 inhibitors (Chk1i) have emerged as promising novel therapeutic agents (1). Chk1 was initially recognized as a regulator of the DNA damage-induced S and G2 checkpoints, and its inhibition forced S phase progression followed by mitotic catastrophe of arrested cells. Subsequently, it was found that the combination of Chk1i with antimetabolites (particularly gemcitabine and cytarabine) more effectively enhanced cell killing (2, 3), and these combinations entered clinical trials. Little clinical benefit has been reported to date, and development of several Chk1i has been terminated for toxicity; whether the toxicity was due to on-target effects remains to be established. It is worth noting one outlier response in which a patient receiving irinotecan and the Chk1i AZD7762 attained a durable response; the sensitivity was tracked to a mutation in RAD50. This suggests that subsets of patients may have therapeutic benefit from this combination (4). Intriguingly, a few cell lines are also highly sensitive to Chk1i as a single agent suggesting subsets of tumors may e...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Invited Abstracts Source Type: research