Abstract 4529: The PI3Kδ inhibitor, idelalisib, inhibits transcription and translation through PI3K/Akt pathway in mantle cell lymphoma
Authors: Qingshan Yang, Lisa S. Chen, Sattva S. Neelapu, Varsha Gandhi
Journal: Cancer Research (2014)

Abstract PI3Kδ is the major PI3K family class I isoform expressed in B-cells that is known to promote cancer cell growth and survival. PI3Kδ pathway is activated through cell surface receptors, e.g. B-cell receptor signaling. This suggests that PI3Kδ is a therapeutic target for B-cell hematological malignancies. Idelalisib is a potent and selective PI3Kδ inhibitor (IC50=19nM) that is currently under investigation in Phase II/III trials in B-cell neoplasms. In solid tumors, it has been established that PI3K/Akt axis regulates transcription and translation processes. Based on the overexpression and hyperactivity of PI3Kδ in B-cell lymphoma such as mantle cell lymphoma (MCL), and PI3Kδ-specific inhibition by idelalisib, we hypothesized that idelalisib treatment will 1) impact the transcription and translation processes that are PI3K/Akt-dependent, 2) disrupt RNA and protein synthetic capacity, and 3) decrease short-lived oncogenic mRNA and proteins levels that are important for MCL cell survival. Idelalisib (0.5 to 5μM) induced modest levels of apoptosis (&amp;lt;15%) in MCL cell lines and primary cells. A reverse-phase protein array (RPPA) study suggested that idelalisib treatment resulted in a decrease in phosphorylation of transcription regulators (GSK-3αβ and c-Myc), and protein synthesis regulators (S6, p70S6K, 4E-BP1, eIF4 and mTOR) in MCL cell lines and primary cells. Immunoblot analysis suggests that a 4hr treatment with idelalisib (0.5 or 1μM) resulted in a decrease of phosphorylated Akt (T308 and S473) levels in both JeKo-1 and Mino cells following IgM stimulation. In parallel, phospho-levels of GSK-3β (S9), 4E-BP1 (S65) and S6 (S235/236) were also decreased. In IgM-stimulated MCL cell lines, moderate to significant decrease in global RNA synthesis (10-15% decrease in JeKo-1, 50% decrease in Mino) and protein synthesis (15% decrease in JeKo-1, &amp;gt;20% decrease in Mino) were detected with 72hr incubation of idelalisib (0.5 to 1μM). Consistent with cell line data, in B-cell lymphoma primary cells, transcription levels were decreased by 20% or &amp;gt;50% following a 24hr treatment with 1 or 5µM idelalisib, respectively; and a 40% decrease of translation level was detected with 5µM idelalisib. In Jeko-1, early response genes MCL1 mRNA level was reduced following 24hr idelalisib treatment, whereas the other mRNAs (PIM2, MYC, CCND1) were decreased to a lesser extent. Mcl-1 and cyclin D1 protein levels were decreased in JeKo-1 and Mino cells following short incubation of idelalisib (0.5 or 1µM). In summary, idelalisib was effective in reducing phosphorylation of Akt and its downstream effectors in MCL cell lines (GSK-3β, 4E-BP1 and S6). Idelalisib inhibits global RNA and protein synthesis, and decreases the levels of short-lived survival proteins. Collectively, these data imply that similar to solid tumors, PI3K regulates key factors involved in gene transcription and protein translation in MCL. Citation Format: Qingshan Yang, Lisa S. Chen, Sattva S. Neelapu, Varsha Gandhi. The PI3Kδ inhibitor, idelalisib, inhibits transcription and translation through PI3K/Akt pathway in mantle cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4529. doi:10.1158/1538-7445.AM2014-4529