Selective inhibition of ATM-dependent double-strand break repair and checkpoint control synergistically enhances the efficacy of ATR inhibitors

by Selleckchem | Sep 17 2023

Ataxia Telangiectasia and Rad3-Related Protein (ATR) kinase regulates a key cell regulatory node for maintaining genomic integrity by preventing replication fork collapse. ATR inhibition has been shown to increase replication stress resulting in DNA double strand breaks (DSBs) and cancer cell death, and several inhibitors are under clinical investigation for cancer therapy. However, activation of cell cycle checkpoints controlled by Ataxia Telangiectasia Mutated (ATM) kinase could minimize the lethal consequences of ATR inhibition and protect cancer cells. Here, we investigate ATR-ATM functional relationship and potential therapeutic implications. In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1 phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell cycle checkpoints and DSB repair, lowered the p53 protective barrier and extended the life of ATR inhibitor induced DSBs. Combination treatment amplified the fraction of cells with structural chromosomal defects and enhanced cancer cell death. ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Further, a combination study in 26 patient-derived xenograft models of triple negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared to single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy.

Comments:

The passage you provided describes the functional relationship between two important kinases involved in maintaining genomic integrity, namely Ataxia Telangiectasia and Rad3-Related Protein (ATR) kinase and Ataxia Telangiectasia Mutated (ATM) kinase. ATR kinase plays a crucial role in preventing replication fork collapse and is involved in regulating cell cycle checkpoints to ensure DNA replication proceeds smoothly. Inhibition of ATR kinase has been shown to increase replication stress, leading to DNA double strand breaks (DSBs) and cancer cell death. Several ATR inhibitors are currently being investigated as potential cancer therapies.

However, the activation of cell cycle checkpoints controlled by ATM kinase can minimize the lethal consequences of ATR inhibition and protect cancer cells. ATM kinase is responsible for detecting DNA damage and initiating a response to repair the damage or induce cell death if repair is not feasible. When ATR kinase is inhibited, ATM kinase activation can help maintain genomic integrity by halting the cell cycle progression at G1 phase, preventing entry into S phase with unrepaired DSBs.

The passage mentions the selective suppression of ATR catalytic activity using an inhibitor called M6620, which induces G1 phase arrest in cancer cells with functional ATM and p53 signaling. This prevents the cells from progressing to S phase with unrepaired DSBs. Additionally, selective ATM inhibitors such as M3541 and M4076 are mentioned, which suppress both ATM-dependent cell cycle checkpoints and DSB repair. These inhibitors lower the protective barrier provided by the tumor suppressor protein p53 and extend the presence of ATR inhibitor-induced DSBs.

Combining ATR and ATM inhibitors leads to an amplification of structural chromosomal defects and enhanced cancer cell death. The ATM inhibitor synergistically potentiates the efficacy of the ATR inhibitor in vitro (in cell culture) and in vivo (in living organisms) at doses that do not cause overt toxicities.

Furthermore, a combination study using the ATR inhibitor M4344 and ATM inhibitor M4076 in patient-derived xenograft models of triple negative breast cancer demonstrated substantial improvement in efficacy and survival compared to using the single-agent ATR inhibitor alone. This suggests that the combination of ATR and ATM inhibitors could be a novel and potentially effective approach to cancer therapy, with potential applicability beyond triple negative breast cancer.

It's important to note that the passage provided is a summary of research findings, and further studies and clinical trials would be necessary to fully understand the therapeutic implications and to validate the effectiveness and safety of this combination approach.