Idelalisib Impacts Cell Growth through Inhibiting Translation-Regulatory Mechanisms in Mantle Cell Lymphoma

Abstract

Purpose PI3 Kinase is a critical node in the B-cell receptor pathway which is responsible for survival and proliferation of B-cell malignancies. Idelalisib, a PI3Kδ-isoform specific inhibitor, has been approved to treat B-cell malignancies. While biological activity of the drug has been evaluated, molecular mechanisms and signaling pathway disruption leading to the biological effects of idelalisib are not yet well-defined. Prior laboratory reports have identified transcription and translation as the primary events for attenuation of PI3Kα isoform. We hypothesized that PI3Kδ-isoform inhibition by idelalisib should also affect gene transcription and protein translation. Experimental Design Using three mantle cell lymphoma cell lines and primary cells from patients, biological consequences such as apoptosis/cell cycle analysis, as well as RNA/protein synthesis were evaluated. Proteomics analyses (RPPA and immunoblot assays) defined molecular events downstream of PI3K/AKT cassette. Results Idelalisib treatment resulted in inhibition of protein synthesis, which correlated with reduction in cell size and cell growth. A moderate loss of viability without any change in cell cycle profile was observed. Idelalisib treatment inhibited AKT activation, an immediate downstream PI3K effector, and also reduced phosphorylation levels of downstream AKT/mTOR pathway proteins such as PRAS40. In addition, idelalisib treatment impeded activation of the MAPK pathway, and MEK, ERK and p90RSK phosphorylation levels were reduced. Reduction in AKT, PDK1, and MEK phosphorylation correlated with protein synthesis inhibition. Conclusions Collectively, these results clarify the molecular mechanisms of actions and may provide biomarkers and targets for combination with idelalisib in B-cell malignancies.

B-cell Receptor Signaling Regulates Metabolism in Chronic Lymphocytic Leukemia

“…Among the four isoforms of PI3K, malignant CLL and other B-cells rely on PI3Kδ/γ, the primary effector of BCR network. Our recent study suggested that in B-cell malignancies, PI3Kδ mimicked a signaling pathway which was previously identified in solid tumors with PI3Kα (8). Several investigations have established that the PI3Kα–mediated signaling cascade influences the cellular metabolome, including glycolysis and energy production (9).…”

Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia

“…Mechanism of duvelisib actions were associated with mitigation of AKT, BAD, ERK, and S6 activity, downstream of the B-cell receptor signaling cascade. Similar inhibitory events were reported in B-cell malignancies with idelalisib [49]. …”

Transcriptional Modulation by Idelalisib Synergizes with Bendamustine in Chronic Lymphocytic Leukemia

“…We observed transcriptional suppression with IDE and IBR treatments in CLL cells in vitro, which was most marked when RNA synthesis was initially increased by CD40/IL4. Similarly, a recent study in mantle cell lymphoma also showed that IDE can inhibit protein synthesis which correlated with a reduction in cell size and growth [28]. While a detailed analysis of the genes effected by IDE in CLL has not yet been carried out, a recent clinical study has demonstrated that the CLL cells of patients receiving IBR show primarily a decrease in genes involved in receptor/cytokines signaling and those expressed in proliferating cells, although increased expression of a subset of genes was also observed [29].…”