Abstract 3915: PBA2, a dual BCR-ABL and GSK3βkinases inhibitor, represses a wide array of Imatinib resistant cell lines in chronic myeloid leukemia

Abstract

Abstract Despite the clinical efficacy of the BCR-ABL (Tyrosine Kinase Inhibitors) TKIs for the treatment of Chronic Myeloid Leukemia (CML), BCR-ABL-T315I mutation still confers higher-level resistance to imatinib and the second generation BCR-ABL TKIs. Ponatinib, as the third generation BCR-ABL TKIs, has the potential activity against CML with T315I mutant BCR-ABL whereas high frequency of serious adverse events limits its clinical use. Through a compound library screen, we identified a novel compound PBA2, a dual kinases inhibitor of GSK3β and BCR-ABL, as a promising agent for the treatment of imatinib-resistant CML. Not only can PBA2 inhibit cell growth but also induce terminal cell differentiation in a series of kinase mutant CML cell lines as well as T315I mutation. Remarkably, the mechanism of action of this compound involved the simultaneous inhibition effect of BCR-ABL and GSK3β, which could be a fruitful approach to suppress the β-catenin/CBP signal pathway that promoted the interaction of β-catenin/p300, leading to growth inhibition and subsequent terminal differentiation. More importantly, we found a novel molecular link between CBP and BCR-ABL. We showed that CBP could regulate BCR-ABL expression through activating CREB which binds to the BCR-ABL promoter in CML cells to start transcription, and the BCR-ABL in turns affect the expression level of CBP. This positive feedback pathway between CBP and BCR-ABL represents a novel way for the treatment of CML, and the novel compound PBA2 targeting at this loop deserves further investigation in clinical trial. Citation Format: Ke Yang, li-Wu Fu. PBA2, a dual BCR-ABL and GSK3βkinases inhibitor, represses a wide array of Imatinib resistant cell lines in chronic myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3915.