Mapping the Progression of Therapy-Induced Senescence to Therapy Tolerance: An Evolutionarily Conserved Mechanism for Optimizing Cancer Treatment with Senotherapeutics.

Therapy-induced senescence (TIS) is a reversible growth arrest induced by anticancer treatments, which may contribute to the development of long-term therapy resistance in tumor cells. Senotherapeutics, agents targeting senescent cells, are being tested in clinical trials to improve patient outcomes. Due to the transient nature of TIS, we hypothesized that senolytics would be most effective when administered at the appropriate time. We created a reliable TIS cell line model in triple-negative breast cancer (TNBC) using experimental drug YM155. We observed that a single dose of YM155 triggers a brief senescence, leading to a persistent drug-tolerant state that cannot be reversed by redosing. This reversibility is not limited to cancer cells. It extends to noncancerous human cells and live zebrafish larvae, suggesting a rapid adaptation mechanism against xenobiotics. We identified transforming growth factor-β (TGF-β), a cytokine linked to TNBC chemoresistance, as being expressed alongside the emergence of drug tolerance. We inhibited TGF-β signaling to eliminate the tolerant phenotype and promote the clearance of cancer cells by immune cells. However, this was most effective within a specific time window after TIS induction. We suggest that the timely use of senotherapeutics could improve the effectiveness of anticancer drugs in clinical settings.