Evaluating the Sensitivity of Sporadic Pancreatic Cancer to poly(ADP-ribose) polymerase (PARP) Inhibition (Velaparib, Olaparib, AG14361) as Single Agents and as Chemo-sensitizers

Abstract

After resection of pancreatic cancer local recurrence occurs in 50%-80% of the cases while metastasis develops 75% of the time. Current, adjuvant therapy often consists of gemcitabine, cisplatin and/or 5-fluorouracil which add a modest increase in median survival by 4-5 months.In this study, we treated human pancreatic cancer cells with poly (ADP-ribose) polymerase (PARP) Inhibitors (AG14361, Veliparib and Olaparib) alone or with gemcitabine, cisplatin or 5fluorouracil. Methods: CFPAC-1 and BXPC-3, HPAC human pancreatic cancer cell lines were treated for 72 hours with PARP inhibitors alone or in combination with gemcitabine, cisplatin, or 5fluorouracil. Validated MTT assays were used to form dose response curves from which the IC50 values were calculated. Results: The PARP1 IC50 values for CFPAC-1, BXPC-3 and HPAC pancreatic cancer cell lines were AG14361 (14.3 µM, 12.7 µM, 38.3 µM), Veliparib (52.6 µM, 100.9 µM 102.0 µM) and Olaparib (79.5 µM, 184.8 µM, 200.2 µM). The IC50 values of cisplatin, were decreased up to 60 fold in the presence of clinically relevant amounts of PARP inhibitor while 5-flourouracil IC50 values were decreased up to 6000 fold in the presence of clinically relevant amounts of PARP inhibitor. Gemcitabine was inhibited up to 73% by PARP inhibitors. Conclusions: Sporadic human pancreatic cancer cells are sensitive to PARP inhibition. PARP inhibitors significantly enhanced the cytotoxicity of cisplatin and 5-fluorouracil while inhibiting gemcitabine. There is little correlation between endogenous PARP activity and the effectiveness of PARP inhibitors.

DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives

“…DNA damage repair pathway deficiency has been shown to confer sensitivity to PARPi. Multiple studies found that the BRCA2 -deficient cell line Capan-1 is significantly more sensitive to several PARP inhibitors and cisplatin, but not to gemcitabine, compared to the BRCA2 -proficient cell lines MiaPaCa-2 and Panc-1 ( Porcelli et al, 2013 ; Andrei et al, 2015 ; de Soto, 2020 ). In addition, restoration of BRCA2 expression in Capan-1 cell lines was shown to reduce sensitivity to olaparib and HYDAMTIQ ( Mini et al, 2017 ; Sullivan-Reed et al, 2018 ).…”