Abstract 7148: Stress adaptation defines therapeutic response to CDK4/6 inhibitors in sarcoma

Abstract CDK4/6 inhibitors are under active clinical evaluation in sarcoma, yet the mechanisms that determine therapeutic sensitivity and resistance remain poorly understood. Here, we show that the CDK4/6 inhibitor abemaciclib not only suppresses tumor cell proliferation but also induces a robust type I interferon (IFN-I) response driven by intracellular double-stranded RNA accumulation—an effect essential for its antitumor activity. Abemaciclib further remodels the sarcoma immune microenvironment by enhancing T cell infiltration and increasing interferon-producing monocytes. Through integrated transcriptomic and proteomic analyses, we identify a stress-adaptive signaling program that is selectively upregulated in tumor cells upon treatment and correlates with poor patient prognosis. Functionally, this pathway mitigates IFN-induced mitochondrial stress, limiting reactive oxygen species accumulation and apoptosis, whereas its suppression exacerbates mitochondrial dysfunction and promotes tumor cell death. In vivo, targeting the adaptive stress-response program synergizes with abemaciclib to inhibit tumor growth and extend survival. These findings define a previously unrecognized mechanism of stress adaptation to CDK4/6 inhibition and highlight a promising strategy to potentiate interferon-driven antitumor responses in sarcoma. Citation Format: Jinfen Xiao, Emily Ko, Ashley Smith, Roberta Piras, Annaliese Fowler, Kristin Ishaya, Jlenia Guarnerio. Stress adaptation defines therapeutic response to CDK4/6 inhibitors in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7148.