Niraparib Suppresses Cholangiocarcinoma Tumor Growth by Inducing Oxidative and Replication Stress

Simple Summary Cholangiocarcinoma (CCA) is a rare and highly aggressive tumor with limited therapeutic options, thus underscoring the need to develop novel therapeutic approaches. We analyzed a publicly available CCA patient database to identify mutations in DNA damage response (DDR) genes. Mutations in DDR genes were prevalent, thus rendering these tumors potentially susceptible to poly-ADP-ribose polymerase (PARP) inhibition. PARP genes are critical to DNA repair and genomic stability. The role of PARP inhibitors in CCA was investigated by employing a series of in vitro functional assays and in vivo patient-derived xenograft models. This study highlights the therapeutic potential of PARP inhibitors alone or in combination with the chemotherapeutic agent gemcitabine for the treatment of CCA. Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer, an aggressive malignancy with limited therapeutic options. PARP (poly (ADP-ribose) polymerase) 1 and 2 are important for deoxyribonucleotide acid (DNA) repair and maintenance of genomic stability. PARP inhibitors (PARPi) such as niraparib have been approved for different malignancies with genomic alteration in germline BRCA and DNA damage response (DDR) pathway genes. Genomic alterations were analyzed in DDR genes in CCA samples employing The Cancer Genome Atlas (TCGA) database. Mutations were observed in various DDR genes, and 35.8% cases had alterations in at least one of three genes (ARID1A, BAP1 and ATM), suggesting their susceptibility to PARPi. Niraparib treatment suppressed cancer cell viability and survival, and also caused G2/M cell cycle arrest in patient-derived xenograft cells lines (PDXC) and established CCA cells harboring DDR gene mutations. PARPi treatment also induced apoptosis and caspase3/7 activity in PDXC and CCA cell lines, and substantially reduced expression of BCL2, BCL-XL and MCL1 proteins. Niraparib caused a significant increase in oxidative stress, and induced activation of DNA damage markers, phosphorylation of CHK2 and replication fork stalling. Importantly, niraparib, in combination with gemcitabine, produced sustained and robust inhibition of tumor growth in vivo in a patient-derived xenograft (PDX) model more effectively than either treatment alone. Furthermore, tissue samples from mice treated with niraparib and gemcitabine display significantly lower expression levels of pHH3 and Ki-67, which are a mitotic and proliferative marker, respectively. Taken together, our results indicate niraparib as a novel therapeutic agent alone or in combination with gemcitabine for CCA.

Automated summary

Cholangiocarcinoma is a rare and aggressive tumor with limited treatment options, but PARP inhibitors show promise as a novel therapy for CCA. Mutations in DNA damage response genes make these tumors susceptible to PARP inhibitors, which can suppress cancer cell viability and induce apoptosis.