Nesuparib enhances anti-tumor efficacy with gemcitabine and nab-paclitaxel in BRCA wild type pancreatic cancer xenograft model

Pancreatic ductal adenocarcinoma is one of the most aggressive and fatal cancer with limited treatment options. The combination of gemcitabine and nab-paclitaxel (GnP) is the first-line treatment for pancreatic cancer, but the median overall survival remains less than a year, and high toxicity limits its use. To address this limitation, we explored whether Nesuparib, a dual inhibitor for poly-ADP-ribosyl transferase 1/2 and tankyrase 1/2, enhances anti-tumor efficacy with GnP in BRCA wild-type pancreatic preclinical models. We first conducted a cell viability assay in BRCA wild-type Mia Paca-2 cells to determine whether Nesuparib increases the cytotoxicity of gemcitabine-based chemotherapy. Combination of Nesuparib with GnP decreased viability by more than 70% compared to GnP treatment alone. In Mia Paca-2 in vivo xenograft model, GnP treatment resulted in 31% tumor growth inhibition (TGI ) compared to the control group, while Nesuparib with GnP elicited TGI by 79%. At the end of the in vivo experiment, changes in various molecules at protein levels were investigated in the separated tumors to characterize plausible mechanisms underlying the significant tumor reduction in Nesuparib with GnP-treated group compared to other treatment groups. Interestingly, c-Myc and MYBL2 levels were increased in the GnP treated one compared to the vehicle control speculating that compensatory mechanisms might be activated after the drug treatment, while these upregulations were restrained by Nesuparib with GnP treatment. We also observed that cyclinD1, beta- Catenin, and RAD51 were decreased in Nesuparib with GnP treatment compared to the control or GnP treatment. Collectively, the data suggests that those molecular modulations are closely associated with the tankyrase inhibition by Nesuparib in BRCA wild-type model, and that combining Nesuparib with the standard chemotherapy further reduces cell proliferation and delays DNA repair compared to chemotherapy alone. Overall, our results suggest that combination with Nesuparib with GnP chemotherapy could be a novel and rational therapeutic option for pancreatic cancer treatment.