PP2A Activation as a Senotherapeutic in Neuroblastoma

Background/Objectives: Therapy-induced senescence (TIS), while initially growth-suppressive, may promote tumor recurrence through the persistence of senescent cells and the senescence-associated secretory phenotype (SASP). Topotecan, a topoisomerase inhibitor and a key component in the treatment of neuroblastoma (NBL), is known to lead to TIS. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that has been linked to cellular senescence. PP2A is downregulated in NBL, primarily through upregulation of its endogenous inhibitors. We have previously shown that a novel small molecule, ATUX-1215, activates PP2A in NBL cells. Methods: The current study investigates the PP2A activator, ATUX-1215, as a senotherapeutic strategy in NBL. Results: We demonstrate that combining ATUX-1215 with topotecan leads to a reduction in senescent cell burden. Combination therapy suppressed PAI-1 and CCL2, key components of the SASP secretome, and enhanced apoptosis. PP2A activation reduced viability, stemness, and clonogenic survival post-TIS. In vivo, the combination of ATUX-1215 treatment with topotecan significantly delayed tumor growth and attenuated the pro-tumorigenic serum SASP. Conclusions: Our findings position PP2A activation as a senotherapeutic approach, transforming the tumor-promoting TIS program into a therapeutic vulnerability, offering a promising avenue to mitigate therapy resistance and improve outcomes in NBL.