Simultaneous Delivery of Dual Inhibitors of DNA Damage Repair Sensitizes Pancreatic Cancer Response to Irreversible Electroporation

Pancreatic ductal adenocarcinoma (PDAC) is an abysmaldisease refractoryto most standard therapies. Irreversible electroporation (IRE) isa local ablative technique for the clinical treatment of solid tumors,including locally advanced and unresectable PDAC, by intratumorallydelivering high-intensity electric pulses to permanently disrupt cellmembranes and induce cell death. But the distribution of electricfield is uneven within the tumor, and in some regions, tumor cellsonly experience temporary perturbation to their cell membrane, a phenomenondenoted as reversible electroporation (RE). These tumor cells maysurvive and therefore are the main culprit of tumor relapse afterIRE. We herein showed that RE, although not killing tumor cells, inducedDNA double-strand breaks and activated DNA damage repair (DDR) responses.Using reactive oxygen species-sensitive polymeric micelles coloadedwith Olaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP),and AZD0156, an inhibitor of ataxia telangiectasia mutated (ATM),the resultant nanoformulation (M-TK-OA) disrupted both homologousrecombination and nonhomologous end joining signaling of the DDR responseand impaired colony formation in pancreatic cancer cells after RE.The combination of IRE and M-TK-OA significantly prolonged animalsurvival in both subcutaneous and orthotopic murine PDAC models andelicited CD8(+) T cell-mediated antitumor immunity with asustained antitumor memory. The efficacy of combined IRE and M-TK-OAtreatments was partially attributed to the activation of cyclic GMP-AMPsynthase-stimulator of interferon genes innate immune responses. Ourstudy suggests that dual inhibition of PARP and ATM with nanomedicineis a promising strategy to enhance the pancreatic cancer responseto IRE.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) is a difficult-to-treat disease. Irreversible electroporation (IRE) is a local ablative technique that can be used to treat locally advanced and unresectable PDAC by disrupting cell membranes with high-intensity electric pulses. However, reversible electroporation (RE) can occur in some regions of the tumor, leading to tumor cell survival and relapse after IRE.