Non-ATP competitive inhibition of PI3Kδ with IOA-244 shows anti-lymphoma activity

Background: Activation of PI3 K signaling, mainly mediated via PI3Kδ,is a fundamental signaling cascade in lymphomas (Tarantelli et al, 2021). IOA-244 (IOA) is highly selective and potent PI3Kδ inhibitor with atypical non-ATP competitive activity (Johnson 2019) compared to FDA-approved inhibitors idelalisib, copanlisib duvelisib. IOA phase 1 as an immunomodulatory agent for patients melanoma, mesothelioma, non-small cell lung cancer, myelofibrosis, follicular peripheral T lymphoma (TCL) single or combination (NCT04328844). doses up 80 mg were well tolerated the first 16 (Di Giacomo Here, we present set data on lymphoma. Materials Methods: Cell lines exposed increasing concentrations anti-proliferative was assessed by MTT assay at 72 h. Apoptosis cycle FACS. Poly-A RNA-Seq performed Illumina system. Results: showed moderate dose-dependent across 74 derived from B (n = 59) TCL 15) IC50 s <1 mM only few lines. lymphomas, particularly mantle (MCL) models (median AUC 666 k; 95% CI: 979–262 n 10), more sensitive than 956 CI 1151– 553 15). Among TCL, cutaneous most sensitive. Compared similar vitro antiproliferative ten MZL, DLBCL MCL. In diffuse large B-cell (DLBCL; 2) MCL lines, induced apoptosis subG0/G1 accumulation already after 48 h 1μM concentration. sensitivity correlated PIK3CD RNA expression all (R −0.32; p 0.014), idelalisib −0.45; 0.053) but not < 0.1; 0.693). cells lymphoma, −0.42; 0.005; R 0.992; 0.73). Transcriptomic analysis RNA-seq revealed that (5 μM; 24, 48, h; SP53 line) downregulated BCR, MYD88, NF-kB, MTOR NOTCH upregulated genes involved arrest (adj.P <10−10). These changes overlapped signatures obtained other BTK 10−10). The down-regulated transcripts 212; abs.fold change>2, adj.P 0.05) included oncogenes (CCND2, TOX, AXL, SGK1, VEGFA) immune-related factors (CCL22, CCL4, CCR1, CXCR3, CSF1, IL2RB, TNFRSF9, SLAMF7, TNF). 188) proapoptotic (HRK, BIK), tumor suppressors (GADD45A, TP63, BACH2), (CXCR4, CTLA4). Conclusions: shows inducing modulating relevant pathways immunotolerance. Conflict interest: Advisory Board: Gilead, AbbVie, Janssen, AstraZeneca, MSD, BMS/ Celgene, Roche, Mei Pharma, Astra Zeneca, Celltrion Healthcare, Incyte, Kite/Gilead Corporate-sponsored Research: Acerta, ADC Therapeutics, Bayer AG, Cellestia, CTI Life Sciences, EMD Serono, Helsinn, ImmunoGen, Menarini Ricerche, NEOMED Therapeutics 1, Nordic Nanovector ASA, Oncology Therapeutic Development, PIQUR Janssen Other Substantive Relationships: Work supported iOnctura SA.