TRAIL Receptor Targeting Agents Potentiate PARP Inhibitor Efficacy in Pancreatic Cancer Independently of BRCA2 Mutation Status

Ben Khaled, Najib; Hammer, Katharina; Ye, Liangtao; Alnatsha, Ahmed; Widholz, Sebastian A.; Piseddu, Ignazio; Sirtl, Simon; Schneider, Julia; Munker, Stefan; Mahajan, Ujjwal Mukund; Montero, Juan Jose; Griger, Joscha; Mayerle, Julia; Reiter, Florian P. und De Toni, Enrico N. (2022): TRAIL Receptor Targeting Agents Potentiate PARP Inhibitor Efficacy in Pancreatic Cancer Independently of BRCA2 Mutation Status. In: Cancers, Bd. 14, Nr. 21

Abstract

Simple Summary Research into pancreatic cancer has identified frequent changes in BRCA genes, especially in BRCA2, occurring in about 5% of patients. BRCA proteins help repair damaged DNA. Pancreatic cancers with alterations in BRCA genes are sensitive to treatment with PARP inhibitors. The PARP inhibitor olaparib can be used to treat pancreatic cancer with mutations in BRCA genes after response to standard platinum-based chemotherapy. Unfortunately, only a few patients with pancreatic cancer have mutations in BRCA genes. In this study, we show that the combination of olaparib and TRAIL can be more effective than olaparib alone in killing pancreatic cancer cells. Furthermore, we demonstrate that the combination of olaparib and TRAIL also kills cancer cells without BRCA2 mutations. Our results suggest a potential new combination therapy of olaparib and TRAIL for pancreatic cancer independent of BRCA2 mutations and may extend the limited applicability of PARP inhibitors in this disease. Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892