Abstract Background: PTEN loss in prostate cancer activates PI3K/AKT/mTOR signaling, driving extensive tumor microenvironment (TME) remodeling characterized by stromal desmoplasia, angiogenesis, and immune suppression. Capivasertib (AZD5363), a potent pan-AKT inhibitor, has shown therapeutic benefit in PTEN-deficient tumors when combined with androgen deprivation therapy (ADT) and abiraterone, as demonstrated in preclinical studies and the Phase III CAPItello-281 trial. Objective: To investigate how AKT inhibition modulates TME dysregulation in PTEN-deficient prostate cancer following AR-targeted therapy. Methods: Conditional Pten-knockout mouse tumors underwent baseline transcriptomic profiling to characterize AKT-driven changes and ADT effects. TME responses were evaluated in conditional Pten/Trp53 knockout mice after four weeks of ADT and abiraterone (Abi), with or without capivasertib. Analyses included qRT-PCR panels, flow cytometry, and quantitative immunohistochemistry (IHC). Results: PTEN deletion induced AKT hyperactivation and upregulated MSigDB hallmark pathways associated with TME remodeling, including hypoxia, angiogenesis, inflammatory response, IL6-STAT3, and TGFβ signaling. ADT amplified these changes, while abiraterone further increased extracellular matrix (ECM) remodeling gene expression. Capivasertib co-treatment significantly downregulated ECM and angiogenesis-related genes. Histological evaluation revealed reduced dense, haphazard collagen deposition and fewer inflammatory infiltrates in capivasertib-treated tumors. IHC confirmed decreased stromal p-S6 and p-PRAS40, lower Ki67-positive stromal cell counts, and reduced microvessel density (CD31). Gene signatures for PMN cells, MDSCs, and TAMs—key mediators of ECM remodeling—were diminished, particularly in mice showing strong antitumor responses to capivasertib. Flow cytometry and IHC corroborated the reduction of PMN/MDSC populations in treated tumors. Conclusion: Capivasertib enhances tumor growth inhibition achieved by ADT plus abiraterone and mitigates TME remodeling associated with PTEN loss and AR-targeted therapy. These findings highlight AKT inhibition as a strategy to counteract TME-driven disease progression and improve therapeutic outcomes. Citation Format: Marco A. De Velasco, Kazuko Sakai, Daiki Nakatsu, Mamoru Hashimoto, Saizo Fujimoto, Shingo Toyoda, Takafumi Minami, Kazuhiro Yoshimura, Simon T. Barry, Cath Eberlein, Claire Rooney, Kazuto Nishio, Hirotsugu Uemura, Kazutoshi Fujita. AKT inhibition with capivasertib counteracts tumor microenvironment remodeling and enhances AR-targeted therapy in PTEN-deficient prostate cancer 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 7170.
Velasco et al. (Fri,) studied this question.