Pharmacological Induction of Irreversible Senescence in Drug-Tolerant Persister Cells Prevents Tumor Relapse

Abstract

Despite substantial advances in targeted therapies, most patients with advanced cancers ultimately relapse. This relapse is frequently seeded by drug-tolerant persister cells (DTPs), which persist as minimal residual disease (MRD) by adopting a reversible quiescent state and later reacquire proliferative capacity under ongoing treatment. To address this, we sought to convert quiescent DTPs into an irreversible, non-proliferative state by pharmacologically inducing senescence. Through large-scale chemical screening and combination optimization, we identified SAHA plus tilorone dihydrochloride (SIC) as a regimen that robustly induces senescence in melanoma DTPs and abolishes their proliferative potential in vitro. Mechanistically, SAHA relieves HDAC1-mediated repression of HMGA2, a key senescence driver, while tilorone synergistically inhibits autophagy to promote a fully senescent state. In a melanoma xenograft mouse model receiving MAPK-targeted therapy, SIC treatment significantly suppressed MRD progression. Importantly, SIC also induced robust senescence across diverse DTP models irrespective of tumor origin, mutational background, or prior treatment. Collectively, these findings provide proof-of-concept that converting DTPs from reversible quiescence to permanent senescence represents an effective strategy to prevent relapse under targeted therapy and position SIC as a broadly applicable pharmacological approach for durable control of residual disease in advanced cancers.