Abstract 2663: Idelalisib impacts cell growth through inhibiting translation regulatory mechanisms in mantle cell lymphoma

Abstract

Abstract Idelalisib, also known as CAL-101 and GS1101, was approved in both the US and EU in 2014 to treat relapsed chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma and follicular lymphoma. In CLL, idelalisib mechanism is not yet well-defined; however, it works in part by disrupting signaling from the tumor microenvironment, including from the B-cell receptor, which contributes to the reduction in lymph node size and increase in lymphocytosis in idelalisib-treated patients. Idelalisib selectively targets PI3Kδ, the predominantly expressed PI3K class IA family member in B-cell malignancies. PI3Kα, the more well-studied PI3K isoform is known to regulate translation and we hypothesized that PI3Kδ may similarly target translation in B-cell malignancies, such as in the aggressive and hard-to-treat mantle cell lymphoma (MCL). Treatment with 0.5-5 μM idelalisib over 24-48h resulted in moderate levels of apoptosis (4-10%), and reduction of both cell number (10-20%) and cell size (15-25%) in 3 MCL cell lines (Jeko-1, Mino, Granta 519). However, the cell size reduction was not cell cycle related. Idelalisib treatment also resulted in global protein synthesis inhibition (10-75%) in MCL cell lines and primary cells as detected by leucine incorporation assay. We confirmed that PI3K/AKT pathway is impacted by idelalisib treatment, as both AKT and GSK-3β phosphorylation were blocked by the treatment. To further examine the mechanism of protein synthesis inhibition, we investigated PI3K downstream pathways that regulate translation including the mTOR pathway. We detected decreased p70S6K (T387) and S6 (S235/236) phosphorylation in MCL cell lines, which are both downstream effectors of mTOR. In addition, we observed consistent reduction of PRAS40 (T246) phosphorylation, which is a binding partner and substrate of both AKT and mTOR. Interestingly, there was a concomitant decrease in p90RSK (T359/S363) phosphorylation, a known effector of MAPK/Erk pathway. P90RSK is directly activated by Erk, and also a regulator of mTOR and S6. In contrast, downstream translation regulator 4E-BP1 phosphorylation was unchanged following idelalisib treatment. Since 4E-BP1 activation is regulated by numerous upstream factors, redundant signaling pathways may be compensating for PI3Kδ inhibition. Consistent with effects on protein translation, preliminary results indicate induction of autophagy by idelalisib, which may be a novel mechanism that has not been previously reported in MCL. Our data provided mechanism of idelalisib-mediated effects on cell growth inhibition and suggest inhibition of protein translation as a potential mechanism. Citation Format: Qingshan Yang, Lisa S. Chen, Sattva S. Neelapu, Varsha Gandhi. Idelalisib impacts cell growth through inhibiting translation regulatory mechanisms in mantle cell lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2663. doi:10.1158/1538-7445.AM2015-2663