ABT-263 Exerts Transient Senolytic Activity Against Therapy-Induced Senescence in NSCLC

Abstract

Therapy-induced senescence (TIS) can suppress tumor growth but may also facilitate long-term relapse through a subset of cells capable of regaining proliferative potential, while the senescence-associated secretory phenotype (SASP) can further promote tumor progression. Senolytic agents, such as the BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax), have therefore emerged as a strategy to selectively eliminate senescent tumor cells. In this study, we evaluated the senolytic efficacy of ABT-263 in murine (CMT-167) and human (A549) non–small cell lung cancer (NSCLC) models following clinically relevant radiation regimens: a single high dose (10 Gy) mimicking stereotactic body radiation therapy (SBRT) and a hypofractionated regimen (2.75 Gy × 4). Both radiation regimens induced a senescent phenotype, although senescence was consistently less pronounced following fractionated irradiation. To determine whether enhanced DNA damage could increase senescence depth and senolytic sensitivity, we combined fractionated radiation with the PARP inhibitor Talazoparib. This combination markedly amplified senescence markers and transiently increased sensitivity to ABT-263. In contrast, combining cisplatin with fractionated radiation failed to enhance senescence induction or senolytic sensitivity beyond cisplatin alone. Across all conditions, despite clear evidence of senolytic activity, ABT-263 consistently failed to achieve durable eradication of senescent cells. A substantial population of cells persisted after treatment while retaining senescence markers. Together, these findings indicate that ABT-263 eliminates only a subset of therapy-induced senescent cells, leaving behind a residual senescent population. This highlights the need for improved strategies to achieve more complete and durable targeting of therapy-induced senescence in NSCLC.