Delving into PARP inhibition from bench to bedside and back

With the ever-expanding therapeutic indications and ongoing clinical trials with Poly(adenosine diphosphate-ribose) Polymerase (PARP) inhibitors, it is of outmost importance to stop and rethink what we know and still do not know concerning one of the major revolutions in target therapies in the last decades. Indeed, many PARP inhibitors (PARPi) are able to bind multiple targets, with a plethora of potential interactions with cancer cell signaling, metabolism and the tumor microenvironment (TME). These interactions can mediate both response and resistance to PARPi, but also represent an opportunity for sequential and/or combinatorial therapies. Here we advocate a “look before you leap” approach in reviewing available clinical and preclinical evidence concerning PARPi, delving into this complex entanglement, trying to unravel the potential for innovative therapeutic strategies revolving on PARP inhibition.