Tumor Cell Recovery from Senescence Induced by Radiation with PARP Inhibition.

Abstract

Inhibitors of poly(ADP-ribose) polymerase (PARP) are clinically used as single-agent therapy for tumors with BRCA1 or BRCA2 mutations. One approach to expanding the use of PARP inhibitors to a wider range of tumors is to combine them with cytotoxic chemotherapy or radiotherapy. Preclinical studies in experimental animals and tumor cells in culture indicate that PARP inhibition modestly sensitizes most tumor cells to ionizing radiation. Studies of cell behavior after these combined treatments show that radiosensitization is manifested predominantly in an increase in prolonged growth arrest and senescence, with little or no contribution from apoptosis. The secretory phenotype associated with senescence can target these tumor cells for immune surveillance, and therefore increased senescence can effectively contribute to tumor control. However, the possible recovery of senescent cells and re-entry into cell cycle after prolonged arrest also needs to be considered. Such recovery could lead to tumor recurrence, yet may not be reflected in short-term assays commonly used to assess radiosensitization.