Talazoparib and radiation enhance the senolytic efficacy of venetoclax in therapy-induced senescent triple-negative breast cancer cells.

Abstract

Triple-negative breast cancer (TNBC) presents ongoing clinical challenges, often leading to relapse in many patients. The relapse is partly explained by tumor cells transitioning into a senescent state following chemotherapy or radiation, resulting in a more aggressive phenotype, contributing to disease recurrence. Consequently, combining senolytics with traditional treatments could be a viable and promising strategy in treating TNBC. To address this, we induced therapy-induced senescence (TIS) both in vitro and in vivo by combining the poly ADP-ribose polymerase (PARP) inhibitor talazoparib with radiation. We tested whether exposure to the senolytic agent, venetoclax, would result in the eradication of senescent cells and augmentation of apoptosis. TIS Markers, like senescence-associated beta-galactosidase (SA-β-gal), CDKN1A, and senescence-associated secretory phenotype (SASP) marker IL-6, were altered following talazoparib and radiation in both 4T1 and MDA-MB-231 TNBC cell lines. Interestingly, venetoclax treatment following TIS induction led to pronounced apoptotic cell death and significant changes in SA-β-gal and IL-6, implying enhanced sensitivity post-senescence induction. Furthermore, these data were validated in vivo in an immunocompetent TNBC-bearing mouse model, in which venetoclax alone had a modest effect on growth inhibition. However, when combined with radiotherapy/talazoparib, venetoclax dramatically interfered with tumor recovery post-senescence induction, indicating a potential strategy to mitigate disease recurrence. These results suggest that combining radiotherapy with PARP inhibitors with senolytic agents such as venetoclax could potentially overcome disease relapse associated with TNBC.