Abstract A018: INPP4B Downregulation and AKT1 Dependence as Emerging Therapeutic Vulnerabilities in TMPRSS2:ERG Fusion Prostate Cancer

Abstract The TMPRSS2:ERG (T:E) gene fusion, present in approximately 50% of prostate cancer (PCa), reprograms androgen receptor (AR)-driven transcription and defines a biologically distinct disease subset. ERG expression has been shown to suppress PI3K/AKT signaling, suggesting that T:E fusion tumors may require compensatory mechanisms to sustain kinase activity. Based on integrative analyses of prostate cancer datasets and preliminary experimental findings, we hypothesize that downregulation of the lipid phosphatase INPP4B provides a nonredundant mechanism to restore AKT activation and promote tumor survival, independent of PTEN loss. We further hypothesize that this adaptive rewiring selectively increases dependence on the AKT1 isoform, creating an opportunity for isoform-specific therapeutic targeting. To test these hypotheses, we combined bioinformatic analysis of TCGA PRAD data with ongoing studies using genetically engineered mouse models, CRISPR interference (CRISPRi)-based perturbation systems, and patient-derived xenografts (PDXs). Functional assays in T:E fusion–positive models were used to evaluate ATA-001, a novel selective AKT1 inhibitor, in comparison with the pan-AKT inhibitor capivasertib. Our preliminary data support the hypothesis that INPP4B downregulation is a hallmark of T:E fusion tumors and may functionally compensate for ERG-mediated repression of PI3K signaling. In these models, AKT pathway activation persisted regardless of PTEN status, consistent with INPP4B loss driving PI(3,4)P2 accumulation. ATA-001, AKT1-specific inhibitor, caused growth inhibition equivalent to capivasertib, accompanied by suppression of pAKT1 and reduced viability in T:E fusion PCa. These findings indicate that AKT1-selective blockade is sufficient to suppress PI3K/AKT signaling in this genomic context. Ongoing CRISPRi screens and mouse model studies are testing the hypotheses that INPP4B loss enhances receptor tyrosine kinase (RTK) signaling and that ERG-INPP4B interactions shape unique signaling dependencies in T:E fusion prostate cancer. Our preliminary results support a model in which ERG expression suppresses PI3K signaling, leading to selective pressure for INPP4B downregulation and AKT1-driven compensation. We propose that this signaling adaptation establishes a therapeutic vulnerability that can be exploited through AKT1-selective inhibition. ATA-001 demonstrates comparable efficacy to pan-AKT inhibition while potentially minimizing toxicity. As AR-targeted therapies downregulate ERG and enhance AKT activation, combination strategies co-targeting AR and AKT1 represent a rational, biomarker-guided therapeutic approach for T:E fusion-positive prostate cancer. Ongoing studies aim to validate these hypotheses and define additional vulnerabilities and resistance mechanisms in this molecularly defined subset. Citation Format: Betul Ersoy-Fazlioglu, Fang Xie, Luigi Cecchi, Isabella Del Priore, Alex Toker, Steven P. Balk. INPP4B Downregulation and AKT1 Dependence as Emerging Therapeutic Vulnerabilities in TMPRSS2:ERG Fusion Prostate Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A018.