Abstract
BackgroundThe ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase 1 (CHK1) pathway plays an essential role in suppressing replication stress from DNA damage and oncogene activation.Main bodyPreclinical studies have shown that cancer cells with defective DNA repair mechanisms or cell cycle checkpoints may be particularly sensitive to ATR inhibitors. Preclinical and clinical data from early-phase trials on three ATR inhibitors (M6620, AZD6738, and BAY1895344), either as monotherapy or in combination, were reviewed.ConclusionData from ATR inhibitor-based combinational trials might lead to future expansion of this therapy to homologous recombination repair pathway-proficient cancers and potentially serve as a rescue therapy for patients who have progressed through poly ADP-ribose polymerase inhibitors.
Highlights
The ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase 1 (CHK1) pathway plays an essential role in suppressing replication stress from DNA damage and oncogene activation
Conclusion the Ataxia telangiectasia and Rad3 related (ATR)-CHK1 pathway in DNA damage response (DDR) has been studied for decades, it was not until recently that the small molecule inhibitors of ATR were developed for the clinical setting [55]
Inhibition of ATR with an ATR inhibitor either as a monotherapy or in combination with DNA- damaging chemotherapy drugs, ionizing radiation, immune checkpoint blockers, or poly (ADP-ribose) polymerase (PARP) inhibitors is being tested in early-phase clinical trials in advanced solid tumors and hematological malignancies
Summary
DNA damage response (DDR) is a complex interconnected signaling network that is essential to defend human genome integrity against a variety of exogenous and endogenous genotoxic insults, such as ultraviolet radiation, ionizing radiation, or reactive oxygen species. Blocking ATR activity would impair DNA repair but would block cell cycle checkpoint activation This double blockade in the DDR against ionizing radiation has been proven to be effective in cancer cell killing in several preclinical models. This dose and schedule were well tolerated with no DLTs observed This combination is being evaluated in a phase 2 multi-arm umbrella study for ATM-deficient NSCLC [49]. Long-term inhibition of ATR signaling severely impaired the ability of cells to use HR-mediated DNA repair [52] These preclinical studies provide the rationale for using an ATR inhibitor/PARP inhibitor combination in HR-proficient and HR-deficient cancer cells. Further clinical investigation of the PARP inhibitor/ ATR inhibitor combination has been extended to multiple phase 2 trials, including the VIOLETTE study on TNBC [54], the SUKSES-N2 study on small-cell lung cancer (NCT03428607), and the CAPRI study on ovarian cancer (NCT03462342). The AZD6738 and olaparib arm requires the preselection of tumors with mutations in HR-DNA repair genes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
