Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice

Abstract

Background:The PI3K–mTOR (phosphoinositide 3-kinase–mammalian target of rapamycin kinase) pathway is activated in the majority of tumours, and there is interest in assessing whether inhibitors of PI3K or mTOR kinase have efficacy in treating cancer. Here, we define the effectiveness of specific mTOR (AZD8055) and PI3K (GDC-0941) inhibitors, currently in clinical trials, in treating spontaneous B-cell follicular lymphoma that develops in PTEN+/−LKB1+/hypo mice.Methods:The PTEN+/−LKB1+/hypo mice were administered AZD8055 or GDC-0941, and the volumes of B-cell follicular lymphoma were measured by MRI. Tumour samples were analysed by immunohistochemistry, immunoblot and flow cytometry.Results:The AZD8055 or GDC-0941 induced ∼40% reduction in tumour volume within 2 weeks, accompanied by ablation of phosphorylation of AKT, S6K and SGK (serum and glucocorticoid protein kinase) protein kinases. The drugs reduced tumour cell proliferation, promoted apoptosis and suppressed centroblast population. The AZD8055 or GDC-0941 treatment beyond 3 weeks caused a moderate additional decrease in tumour volume, reaching ∼50% of the initial volume after 6 weeks of treatment. Tumours grew back at an increased rate and displayed similar high grade and diffuse morphology as the control untreated tumours upon cessation of drug treatment.Conclusion:These results define the effects that newly designed and specific mTOR and PI3K inhibitors have on a spontaneous tumour model, which may be more representative than xenograft models frequently employed to assess effectiveness of kinase inhibitors. Our data suggest that mTOR and PI3K inhibitors would benefit treatment of cancers in which the PI3K pathway is inappropriately activated; however, when administered alone, may not cause complete regression of such tumours.

Involvement of the Syk–mTOR pathway in follicular lymphoma cell invasion and angiogenesis

“…[46][47][48][49][50] It would be very interesting to test the combination of a Syk inhibitor with PI3K or mTOR inhibitors such as GDC-0941 or AZD8055, respectively, which have demonstrated beneficial effects in a spontaneous B-cell FL model. 51 Syk is also known to activate downstream targets involved in cell migration, such as FAK, PYK2 and ezrin. 5,52,53 FAK and PYK2 kinases are upstream of PI3K/Akt 54,55 and therefore potentially connect Syk and PI3K-mTOR; however, we were unable to establish a role for them in MMP-9 expression and FL cell migration using siRNA or pharmacological inhibitors.…”

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

“…91 As a single agent or in combination with other compounds, GDC-0941 induced apoptosis in AML cells under hypoxic conditions, which suggests efficacy in targeting residual AML cells sequestered in a hypoxic bone marrow microenvironment. 92 In MCL tumor samples, GDC-0941 blocked proliferation and induced apoptosis more effectively than the p110d-specific inhibitor, idelalisib.…”

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

“…Mouse models have demonstrated that LKB1 loss can also cooperate with PTEN loss to drive the tumorigenesis of a (19). Pan-PI3K inhibitors and mTORC1/2 inhibitors have each been shown to instigate temporary tumor regression in mice with concurrent PTEN/LKB1 deficiencies; however, the effect of combining PI3K and mTOR inhibition, either together, or with other forms of inhibition, has yet to be investigated (20).…”