Background: Oncogene-driven high-grade serous ovarian cancers (HGSOC) with CCNE1 or MYCN pathway activation exhibit defective cell cycle checkpoint control and replicative stress (RS). The DNA damage response effector kinase, Chk1, modulates the cellular response to RS and has been shown to be upregulated in these subtypes of HGSOC. SRA737 is a novel, potent, highly selective and orally available Chk1 inhibitor that is currently under clinical investigation in high-RS cancers including HGSOC. We explored the efficacy of single agent SRA737 at three doses compared to olaparib, a PARP inhibitor recently approved for HGSOC, in our preclinical HGSOC models.Methods: Two HGSOC patient derived xenografts (PDX) with defined clinicopathologic and molecular characteristics hypothesized to have high intrinsic RS were selected for in vivo drug testing. PDX #111 was generated from a HGSOC with 59-fold amplification of CCNE1 while PDX #29 has a 9-fold amplification of CCNE1 and over-expression of the MYCN pathway. Both HGSOCs were refractory to standard platinum-based therapy and were WT for BRCA1/2 and related gene mutations. Upon reaching treatment size (180 to 300 mm3), mice bearing PDX tumors were randomized to daily treatment for 21 days with SRA737 (100 mg/kg, 50 mg/kg, or 25 mg/kg), olaparib (100 mg/kg) or vehicle. Tumor volume was monitored until the experimental endpoint of 700 mm3, or 120 days post completion of therapy was reached. Short term harvest (STH) experiments were also performed following a single dose of SRA737 of 100 mg/kg or 50 mg/kg. Tumors were collected at 12 hours following treatment to determine on-target drug effects. Results: Treatment of PDX #111 with SRA737 at 100 mg/kg resulted in significant stabilization of disease, leading to prolonged median time to harvest (TTH) of 78 days for SRA737 vs. 43 days for vehicle (p value < 0.001). As expected, olaparib treatment was less effective and inferior than SRA737 at 100mg/kg (TTH = 46 days; p value < 0.001) given the absence of BRCA1/2 mutations in this model. Impressively, in PDX #29, SRA737 at 100 mg/kg resulted in tumor regression leading to improved median TTH and outperforming olaparib (median TTH of 81 days for SRA737 100 mg/kg, 46 days for olaparib and 39 days for vehicle; p value < 0.05 for both). Analysis of cell cycle and RS biomarkers in the STH samples is underway.Conclusion: Chk1 inhibition by SRA737 shows promising efficacy in CCNE1-amplified and MYCN-overexpressing preclinical PDX models of HGSOC, where other targeted therapies such as PARP inhibitors show limited activity. These in vivo data support the ongoing monotherapy clinical trial of SRA737, which includes the prospective enrollment of patients with these HGSOC subtypes.
- Chk1 inhibition