ECE2016 Eposter Presentations Endocrine tumours and neoplasia (68 abstracts)
Dual inhibition of PI3K and mTORC1/C2 by PKI-587 (PF-05212384) as a promising therapeutic option for pulmonary neuroendocrine tumor disease
Vanessa Bröker 1, , Helma Freitag 1 , Friederike Christen 1, , Franziska Briest 1, , Britta Siegmund 1 & Patricia Grabowski 1,
1Charité, Berlin, Germany; 2Universität, Bonn, Germany; 3Department of Chemistry and Biochemistry, Freie Universität (FU), Berlin, Germany; 4Zentralklinik bad Berka, Bad Berka, Germany; 5Institute of Biology, Humboldt-Universität, Berlin, Germany.
Background: Pulmonary neuroendocrine neoplasms are heterogeneous in their clinical behavior and therapeutic options are still not satisfactory. The ‘crosstalk’ of different signaling pathways in NEN cells appears to be more complex as known already. PKI-587 is a highly potent novel dual inhibitor of PI3K and mTORC1/C2.
Aim: Therefore, we assessed the effects of PKI-587 in different pulmonary NEN cell lines compared to the established mTORC1 inhibitor RAD001 and the non-neuroendocrine lung cell line A549.
Materials and Methods: We treated the cell lines NCI-H727, NCI-H69 and A549 with increasing concentrations of the inhibitor PKI-587, compared to RAD001 and DMSO. We performed MTS cell proliferation assay to determine efficacy and growth inhibition. The induction of apoptosis was shown by caspase 3/7 activation and cell cycle was analyzed by FACS. A JC-1 assay was additionally held out to show occurrence of early apoptosis.
Results: In all cell lines PKI-587 inhibited dose-dependently proliferation with an IC50 of approx. 30 – 6000 nM, whereas RAD001 was less effective. Treatment with PKI-587 led to cell cycle arrest in all cell lines and induction of apoptosis in NCI-H727 and NCI-H69 cells, whereas no apoptosis was observed in non-neuroendocrine A549 tumor cells.
Conclusion: PI3K/mTOR dual targeting is a promising new therapeutic approach in neuroendocrine tumor disease. Protein analysis with Western Blot will be held out in the next weeks and presented at the meeting. The efficacy of PKI-587 should be evaluated in further clinical trials.
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