ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib
AZD6738 (ceralasertib) is really a potent and selective orally bioavailable inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. ATR is activated as a result of stalled DNA replication forks to advertise G2-M cell-cycle checkpoints and fork restart. Here, we found AZD6738 modulated CHK1 phosphorylation and caused ATM-dependent signaling (pRAD50) and also the DNA damage marker ?H2AX. AZD6738 inhibited break-caused replication and homologous recombination repair. In vitro sensitivity to AZD6738 was elevated in, although not only at, cells with defects within the ATM path or that harbor putative motorists of replication stress for example CCNE1 amplification. This converted to in vivo antitumor activity, with tumor control requiring continuous dosing and free plasma exposures, which correlated with induction of pCHK1, pRAD50, and ?H2AX. AZD6738 demonstrated combinatorial effectiveness with agents connected with replication fork stalling and collapse for example carboplatin and irinotecan and also the PARP inhibitor olaparib. These combinations needed optimization of dose and schedules in vivo and demonstrated superior antitumor activity at lower doses in contrast to that needed for monotherapy. Tumor regressions needed a minimum of a couple of days of daily dosing of AZD6738 concurrent with carboplatin, while two times daily dosing was needed following irinotecan. Inside a BRCA2-mutant patient-derived triple-negative cancer of the breast (TNBC) xenograft model, complete tumor regression was achieved with 3 to5 times of daily AZD6738 each week concurrent with olaparib. Growing olaparib dosage or AZD6738 dosing to two times daily permitted complete tumor regression even just in a BRCA wild-type TNBC xenograft model. These preclinical data provide rationale for clinical look at AZD6738 like a monotherapy or combinatorial agent.
Significance: This detailed preclinical analysis, including pharmacokinetics/pharmacodynamics and dose-schedule optimizations, of AZD6738/ceralasertib alone and in conjunction with chemotherapy or PARP inhibitors can inform ongoing clinical efforts to deal with cancer with ATR inhibitors.