PARP inhibitors induce a senescence phenotype in non-small cell lung carcinoma cell lines

Several Anticancer treatments have been shown to activate the DNA damage repair pathway but also, in some cases, to lead to therapy-induced senescence. Senescent cells can either exert protumoral or antitumoral effects. However, it remains poorly characterized which treatments lead to a senescent state. Our findings identify Talazoparib, a PARP1 Inhibitor, as the most potent inducer of senescence in nonsmall cell lung carcinoma cell lines among a variety of PARP1 inhibitors. In the absence of PARP1, no senescence phenotype was observed, thus demonstrating that PARP1 is necessary for the induction of senescence in nonsmall cell lung carcinoma cells exposed to Talazoparib. This enzyme is also required to induce an increase in cell death with the addition of Navitoclax (ABT-263), a senolytic drug. As senescence has been shown to have several protumoral effects, these results demonstrate the importance of determining which Anticancer therapies induce a senescence phenotype as it could lead to not only treatment failure but alsodrug combinations targeting this pathway to further enhance Anticancer treatment efficacy.

PARP inhibitors; lung cancer; senescence; senolytics.