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

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+/-LKBI+/hypo mice.METHODS: The PTEN+/-LKBI+/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 similar to 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 similar to 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.British Journal of Cancer (2011) 104, 1116-1125. doi: 10.1038/bjc.2011.83 www.bjcancer.comPublished online 15 March 2011 (c) 2011 Cancer Research UK