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Reverse phase protein microarray for identification of IL6 receptor ligation-induced insulin receptor, PI3K/AKT, and JAK/STAT signaling pathways in the CARD11 mutated lymphoma cell line OCI-Ly3.
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: A subset of diffuse large B cell lymphoma of the activated B cell subtype bear mutations that drive B cell antigen receptor (BCR) independent chronic activation of NFkB. The consequence appears to be loss of dependency for survival on BCR proximal kinases (BTK, SYK) and the initiation of a cytokine autocrine stimulation loop conferring an alternate survival mechanism. In the OCILy3 cell line, for example, IL6 is produced de novo as a consequence of NFkB gene transcription, and both neutralizing anti-IL6 antibody and small molecule JAK inhibition affects cell survival. The exact nature of this survival mechanism, however, is unclear. The goal of our studies was to more clearly define the molecular events induced by IL6 stimulation that promote survival inOCILy3 DLBCL. Methods: Reverse phase protein microarray is a high throughput methodology to evaluate multiple intracellular phosphoryaltion events in whole cell lysates. Using a panel of 180 phospho-specific antibodies, we assessed phosphorylation events in OCILy3 cells following IL6 receptor stimulation with and without treatment with the dual SYK/JAK inhibitor PRT062070 (Cerdulatinib). Results: 28 of the 180 phosphorylation events tested were induced by approximately 20% or greater upon IL6 receptor stimulation. The most heavily represented categories were within the PI3K/AKT/mTOR, insulin receptor, and JAK/STAT signaling pathways. This was evidenced most notably by robust IL6-mediated induction of Akt, Foxo3a, insulin growth factor receptor and insulin substrate, as well as STAT3 and STAT5 phosphorylation. Treatment with PRT062070 completely inhibited these phosphorylation events. Moreover, PRT062070 dramatically reduced basal phosphorylation of STAT3 Y705, Foxo3a S253, S6Rb S235/236, NFkB p65 S536, BIM S69, and BCL2 T56, and inhibited OCILy3 survival. Conclusions: We conclude from these data that in a subset of B cell lymphomas, IL6 receptor signaling likely contributes to survival via induction of multiple signaling arms, not limited to JAK/STAT pathway activation.
Abstracts by Greg Coffey:
Cerdulatinib (PRT062070): A dual SYK/JAK inhibitor in patients with relapsed/refractory b-cell malignancies—Pharmacokinetic and pharmacodynamic outcomes with twice-daily (BID) vs once-daily (QD) dosing.Meeting: 2016 ASCO Annual Meeting | Abstract No: 7557
Phase 1 open-label dose escalation study of the dual SYK/JAK inhibitor cerdulatinib (PRT062070) in patients with relapsed/refractory B-cell malignancies: Safety profile and clinical activity.Meeting: 2015 ASCO Annual Meeting | Abstract No: 8531
Pharmacokinetics and pharmacodynamics of the dual syk/jak inhibitor PRT062070 (cerdulatinib) in patients with advanced B-cell malignancies.Meeting: 2014 ASCO Annual Meeting | Abstract No: 2619