Hepatocellular carcinoma (HCC) cells critically depend on PARP1 and CHK1 activation for survival. Combining the PARP inhibitor (PARPi) olaparib with a CHK1 inhibitor (MK-8776, CHK1i) produced a synergistic effect, reducing cell viability and inducing marked oxidative stress and DNA damage, particularly in the HepG2 cells. This dual treatment significantly increased apoptosis markers, including γH2AX and caspase-3/7 activity. Both HCC cell lines exhibited heightened sensitivity to the combined treatment. The effect of drugs on the expression of proliferation markers in an olaparib-resistant patient-derived xenograft (PDX) model of ovarian cancer was also investigated. Ovarian tumors displayed reduced tissue growth, as reflected by a drop in proliferation marker Ki-67 levels in response to PARPi combined with CHK1i. No changes were observed in corresponding liver tissues using Ki-67 and pCHK staining, which indicates the absence of metastases and a hepatotoxic effect. Thus, our results indicate that the dual inhibition of PARP and CHK1 may prove to be a promising therapeutic approach in the treatment of primary HCC as well as OC tumors without the risk of liver metastases, especially in patients with olaparib-resistant tumor profiles.

Department of Cytobiochemistry Institute of Biochemistry Faculty of Biology and Environmental Protection University of Lodz 90 236 Lodz Poland

Department of Experimental Immunology Maria Sklodowska Curie National Research Institute of Oncology 5 Roentgena Street 02 781 Warsaw Poland

Department of Genetics Maria Sklodowska Curie National Research Institute of Oncology 5 Roentgena Street 02 781 Warsaw Poland

Department of Medical Biophysics Institute of Biophysics Faculty of Biology and Environmental Protection University of Lodz 90 236 Lodz Poland

Doctoral School of Exact and Natural Sciences University of Lodz Jana Matejki 21 23 90 237 Lodz Poland

Faculty of Science University of Jan Evangelista Purkyně in Ústí nad Labem 400 96 Ustí nad Labem Czech Republic

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