CDK4/6 inhibition exploits the radiobiology of lutetium-177 therapy to induce replication stress and durable senescence

Abstract Background Lutetium-177 ( 177 Lu)-based radiopharmaceutical therapy delivers prolonged low-dose-rate irradiation, creating a radiobiological context that differs substantially from conventional external beam radiotherapy (EBRT). We hypothesised that this extended radiation exposure generates distinct therapeutic vulnerabilities and senescence states that can be exploited pharmacologically. Methods A high-throughput clonogenic screen of 295 small-molecule inhibitors was performed in combination with 177 Lu-DOTATATE and compared with equitoxic EBRT. Candidate interactions were validated using multiple CDK4/6 inhibitors across SSTR2- and PSMA-targeted neuroendocrine and prostate cancer models, including xenografts. Cell-cycle regulation, replisome stability, DNA damage, p21 dynamics, senescence and autophagy-associated nuclear processing were interrogated mechanistically. Results Drug interactions with 177 Lu-DOTATATE differed substantially from those observed with EBRT, identifying CDK4/6 inhibition as a preferential therapeutic vulnerability of prolonged 177 Lu exposure. Abemaciclib, palbociclib and ribociclib enhanced clonogenic suppression by 177 Lu-DOTATATE, while abemaciclib similarly potentiated 177 Lu-PSMA in human prostate cancer models and improved tumour control in vivo. Therapeutic cooperation was not associated with enhanced Rb inhibition or G1 arrest, but with replisome depletion, replication stress, genotoxicity and durable senescence. Distinct senotypes emerged between tumour models: 22Rv1 cells developed a predominantly sustained p21 high state associated with persistent growth arrest, whereas CA20948 cells displayed a p21 low senotype following an early p21 response, accompanied by increased autophagic and nucleophagic features. Pharmacological inhibition of autophagy differentially altered these senotypes, indicating that divergent p21-processing states can converge on durable senescence following combined CDK4/6 inhibition and 177 Lu therapy. Conclusions CDK4/6 inhibition exploits a therapeutic vulnerability created by prolonged 177 Lu irradiation by promoting replication stress and durable senescence rather than conventional cell-cycle arrest. The emergence of distinct p21 high and p21 low senotypes identifies senescence heterogeneity as a previously underappreciated determinant of radiopharmaceutical response and provides a mechanistic rationale for combining clinically established CDK4/6 inhibitors with 177 Lu-based therapy.