Pharmacological strategies for the mitigation of the negative effects of cellular senescence

Cellular senescence is a state of stable cell cycle arrest that occurs in response to persistent cellular damages and which is accompanied by an altered secretome. The prolonged and aberrant persistence of senescent cells is often associated with tissue dysfunction and pathology, including both in cancer and aging. The aim of this thesis was to identify exploitable molecular targets correlated with cellular senescence and whose pharmacological targeting may attenuate the deleterious effects associated with the accumulation of senescent cells. To achieve this, we first set-out to define cellular senescence and to outline the contribution of senescent cells to tumorigenesis, tissue dysfunction, and pathology. Having outlined the negative contributions of persistent senescent cells to both cancer and aging, we described existing pharmacological interventions that aim to selective eliminate them, also known as ‘senolytic’ drugs. In order to develop new senolytic interventions we focused on identifying the main molecular players involved in promoting senescent cell survival, with a particular emphasis on senescence-associated anti-apoptotic pathways. Given the described mechanisms that senescence cells activate in response to chemotherapy and radiation, we decided to study (1) the extrinsic route of apoptosis, (2) the role of MIF in the senescence-associated secretory phenotype (SASP), and (3) the role of oncogenic EGFR/ADAM17 siganling. The results of these experimental studies are described in this thesis.