Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have become a mainstay of therapy in ovarian cancer and other malignancies, including BRCA-mutant breast, prostate, and pancreatic cancers. However, a growing number of patients develop resistance to PARPis, highlighting the need to further understand the mechanisms of PARPi resistance and develop effective treatment strategies. Targeting cell cycle checkpoint protein kinases, e.g., ATR, CHK1, and WEE1, which are upregulated in response to replication stress, represents one such therapeutic approach for PARPi-resistant cancers. Mechanistically, activated cell cycle checkpoints promote cell cycle arrest, replication fork stabilization, and DNA repair, demonstrating the interplay of DNA repair proteins with replication stress in the development of PARPi resistance. Inhibitors of these cell cycle checkpoints are under investigation in PARPi-resistant ovarian and other cancers. In this review, we discuss the cell cycle checkpoints and their roles beyond mere cell cycle regulation as part of the arsenal to overcome PARPi-resistant cancers. We also address the current status and recent advancements as well as limitations of cell cycle checkpoint inhibitors in clinical trials. 

http://manuscript.elsevier.com/S1043661822001074/pdf/S1043661822001074.pdf

Cell Cycle Checkpoints and Beyond: Exploiting the ATR/CHK1/WEE1 Pathway for the Treatment of PARP Inhibitor-Resistant Cancer.

DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.

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Therapeutic Targeting of DNA Damage Response in Cancer

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/1878-0261.13224

Resistance to DNA repair inhibitors in cancer

ABSTRACT Introduction Ataxia telangiectasia and RAD3-related kinase (ATR) is one of the key phosphatidylinositol 3-kinase-related kinase family members important for DNA damage response and repair pathways. Targeting ATR kinase for potential cancer therapy has attracted a great deal of attention to both pharmaceutical industries and academic community. Area covered This article surveys the patents published since 2014 aiming to analyze the structural features of scaffolds and the patent space. It also discusses the recent clinical developments and provides perspectives on the challenges and the future directions. Expert opinion ATR kinase appears to be a viable drug target for anticancer therapy. Similar to DNA-PK inhibitors, the clinical investigation of an ATRi employs both monotherapy and combination strategy. In the combination strategy, an ATRi is typically combined with a radiation or a targeted drug such as chemotherapy agent poly (ADP-ribose) polymerase (PARP) inhibitor, etc. Diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl to macrocycle are capable of achieving good ATR inhibitory activity and good ATR selectivity over other closely related enzymes. There are eight ATR inhibitors currently being evaluated in clinics, with the hope to get approval in the near future.

Discovery of small-molecule ATR inhibitors for potential cancer treatment: a patent review from 2014 to present

Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11.

Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer for predicting activity, and most effective therapeutic combinations Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids, and mouse xenograft models We also elucidated the anticancer mechanisms and potential biomarkers for M4344 We demonstrate that M4344 is highly potent among the clinically developed ATR inhibitors Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment M4344 kills cancer cells by inducing cellular catastrophe and DNA damage M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models Taken together, M4344 is a promising and highly potent ATR inhibitor It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin, and talazoparib RepStress and NE gene expression signatures can be exploited as predictive markers for M4344

/pdf/novel-and-highly-potent-atr-inhibitor-m4344-kills-cancer-3un5ez3llx.pdf

Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents

Ilya S. Senatorov

Papers

Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents