Removing therapy-induced senescent cancer cells targets and potentiates the response of pancreatic cancer cells toward PARP inhibitors as maintenance therapy.

Poly (ADP‒ribose) polymerase inhibitors (PARPis) are widely used in maintenance therapy for various platinum-sensitive cancers regardless of the occurrence of BRCA mutations. However, the mechanisms of action and treatment resistance associated with the use of PARPis for maintenance therapy in pancreatic cancer remain unclear. In this study, in addition to the induction of apoptosis, the use of PARPis (olaparib and niraparib) as maintenance therapies inhibited cell proliferation by causing cellular senescence to exert potent anticancer effects on Capan-1 (BRCA mutated) and PANC-1 (BRCA wild-type) cells. Mechanistically, the cellular senescence caused by PARPis relies on the Chk2‒p21 pathway but not in a p53-dependent manner. Interestingly, in addition to directly causing DNA damage, PARPis also exacerbate DNA damage through the generation of ROS via the positive feedback pathway, thereby inducing cellular senescence. Unfortunately, PARPis therapy-induced senescence is a reversible anticancer mechanism in which senescent cancer cells lose their senescence-like phenotype and continue proliferating upon drug withdrawal. This potentially explains the requirement for sustained PARPi therapy in the clinic. Furthermore, the expression of Bcl-2 was increased in PARPi-induced senescent cancer cells, providing a window for opportunistic elimination via synergistic senolytic drugs. The inhibition of Bcl-2 through the sequence-dependent combination of navitoclax enhanced the anticancer effects of PARPis by removing senescent cells. Collectively, data from our study demonstrate that the clinical application of PARPis as maintenance therapy could be achieved through the induction of cellular senescence. Furthermore, sequence-dependent combination with senescence-targeting drugs can potentiate pancreatic cancer treatment effects of PARPis regardless of the BRCA status.