Cellular senescence in the response of HR+ breast cancer to radiotherapy and CDK4/6 inhibitors

Cellular senescence, an irreversible cell cycle arrest that is accompanied by the abundant secretion of cytokines and other bioactive factors (a process commonly referred to as senescence-associated secretory phonotype [SASP]), has been attributed beneficial as well as detrimental effects on the sensitivity of various tumors to therapy, with a considerable degree of context dependency. Since both RT and CDK4/6 inhibitors elicit cellular senescence as part of their in vivo effects, we hypothesized that the differential efficacy of RT followed by (→) P vs P→RT could depend on the differential accumulation of senescent cells in the tumor microenvironment (TME). Here, we demonstrate that the elimination of senescent (p16+) cells by a genetic approach ameliorates the efficacy of P→RT (without a significant effect on RT→P) in an immunocompetent model that recapitulates key immunobiological features of human HR+ breast cancer. Consistent with this notion, RT→P induced less cellular senescence than P→RT in cultured human and mouse breast cancer cell lines. Thus, a program of cellular senescence may negatively influence the sensitivity of HR+ breast cancer to RT combined with CDK4/6 inhibitors, a possibility that awaits validation in other experimental systems.