Idelalisib activates AKT via increased recruitment of PI3Kδ/PI3Kβ to BCR signalosome while reducing PDK1 in post-therapy CLL cells.

Autor: Mamidi MK; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Mahmud H; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Maiti GP; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Mendez MT; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Fernandes SM; Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Vesely SK; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Holter-Chakrabarty J; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Brown JR; Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Ghosh AK; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. asish-ghosh@ouhsc.edu.; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. asish-ghosh@ouhsc.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2022 Jul; Vol. 36 (7), pp. 1806-1817. Date of Electronic Publication: 2022 May 14.
DOI: 10.1038/s41375-022-01595-0
Abstrakt: Idelalisib targets PI3Kδ in the BCR pathway generating only a partial response in CLL patients, indicating that the leukemic cells may have evolved escape signals. Indeed, we detected increased activation of AKT accompanied by upregulation of MYC/BCL2 in post-therapy CLL cells from patients treated with idelalisib/ofatumumab. To unravel the mechanism of increased AKT-activation, we studied the impact of idelalisib on a CLL-derived cell line, MEC1, as a model. After an initial inhibition, AKT-activation level was restored in idelalisib-treated MEC1 cells in a time-dependent manner. As BCAP (B-cell adaptor for PI3K) and CD19 recruit PI3Kδ to activate AKT upon BCR-stimulation, we examined if idelalisib-treatment altered PI3Kδ-recruitment. Immunoprecipitation of BCAP/CD19 from idelalisib-treated MEC1 cells showed increased recruitment of PI3Kδ in association with PI3Kβ, but not PI3Kα or PI3Kγ and that, targeting both PI3Kδ with PI3Kβ inhibited AKT-reactivation. We detected similar, patient-specific recruitment pattern of PI3K-isoforms by BCAP/CD19 in post-idelalisib CLL cells with increased AKT-activation. Interestingly, a stronger inhibitory effect of idelalisib on P-AKT (T308) than S473 was discernible in idelalisib-treated cells despite increased recruitment of PI3Kδ/PI3Kβ and accumulation of phosphatidylinositol-3,4,5-triphosphate; which could be attributed to reduced PDK1 activity. Thus, administration of isoform-specific inhibitors may prove more effective strategy for treating CLL patients.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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