Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

Abstract

Peripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy. New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol-3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol-3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas. Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T-cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot. The PIK3CD gene, which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3b and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC-0941-treated T-cell lymphoma cell lines, suggesting the presence of a combination of phosphatidylinositol-3-kinase and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T-cell lymphoma cell lines, and reducing cell viability in primary tumor T cells ex vivo. These results suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T-cell lymphomas. ©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.068510 Simultaneous inhibition of pan-phosphatidylinositol-3-kinases and MEK as a potential therapeutic strategy in peripheral T-cell lymphomas

EphB and ephrin-B interactions mediate human mesenchymal stem cell suppression of activated T-cells

“…Our findings are also supported by a recent study showing that reverse ephrin-B signaling inhibited MSC attachment and spreading by activating Src-, PI3Kinase-and JNK-dependent signaling pathways [14]. However, it should be mentioned that the general effect observed in T-cell suppression through the inhibition of Src, PI3K, JNK, and Abl pathways has previously been reported for a variety of other cell types unrelated to Eph/ephrin signaling [65,[72][73][74][75][76][77][78][79][80]. Nevertheless, we observed a consistent suppression of T-cell proliferation after treatment with either EphB2-Fc or ephrin-B2-Fc compared with human-Fc control in the presence of Src, Abl, PI3Kinase, or JNK inhibitors.…”

The RHOA G17V gene mutation occurs frequently in peripheral T-cell lymphoma and is associated with a characteristic molecular signature

“…8,9 The findings presented here suggest that RHOA-G17V could identify patients who are sensitive to some of these inhibitors. Further clinical and biological studies are needed to validate these results.…”

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

“…Objective response rates were seen in about 50% of the patients with relapsed or refractory B-cell malignancies (41,42). Although GS-1101 shows great potential as a candidate therapy for CLL and NHL, some recent studies with experimental models have suggested that pan-class I PI3K inhibition could offer broader activity in a variety of hematologic malignancies (43)(44)(45). Such observations should be treated with caution: although GS-1101 demonstrated moderate activity during preclinical development, it has shown impressive activity in the clinical setting, which has been attributed to its action on the tumor microenvironment, as opposed to its activity within leukemia and lymphoma cells themselves (46).…”