Abstract 4528: Comparison of anti-proliferation activity of BEZ 235, a multi-step inhibitor of mTOR pathway, vs. BKM120, a pan PI3K inhibitor, in lung cancer cell lines (LCCL)

Abstract Background: PI3K/AKT/mTOR(Mammalian target of rapamycin) signal transduction pathway is over-activated in many cancers including lung cancers. The activation of cell surface receptors i.e.EGFR (Epidermal Growth Factor Receptor) signals through PI3K/AKT/mTOR pathway which then results in increase cell proliferation, angiogenesis and anti-apoptosis process. BEZ 235 is a multi-step inhibitor of PI3K and mTORC 1 / 2. BKM 120 is a novel pan class I PI3K inhibitor of all class I PI3K isoforms (α, β, Υ, δ). Inhibition of multiple steps of PI3K/AKT/mTOR pathway would be advantageous and could yield higher activity and overcome over activation of PI3K/AKT, a potential mechanism of resistance to mTOR inhibitors. Docetaxel (D) is an approved agent used in the treatment of lung cancer. We previously demonstrated that the sequence of D followed by mTOR inhibitor temsirolimus (T) in lung cancer cell lines (LCCL) had increased suppression of cell proliferation as compared to reverse sequence of T→D due to suppression of over-activation of PI3K/AKT resistance mechanism. We studied the anti-proliferation effect of each compound in LCCL and also compared the activity of sequential docetaxel followed by BKM 120 vs. D followed by BEK235. Methods: Adenocarcinoma LCCL H2122 and A549 were treated with increasing concentrations of BEZ 235 (50nM, 75 nM, 100 nM) and BKM 120 at same concentrations. Both agents were provided by Novartis.We assessed the cell proliferation by optical density. In the sequential treatment study, we incubated LCCL with D 100nM for 24h then added BKM 120 or BEZ235 at 50nM, 75nM and 100nM. We then assessed the anti-proliferation effect at 48h and 72h. Results: BEZ 235 single had greater inhibitory effect in LCCL proliferation as compared to BKM120. The sequential treatment of D followed by BEZ235 or BKM120 did not yield higher anti-proliferation effect compared to single agent treatment in both LCCL. Conclusion: Single agent BEZ235 had greater anti-proliferation effect than BKM120 in both LCCL. The sequential treatment of D followed by BEZ235 or BKM120 did not lead to increased anti-proliferation effect. The potential explanation of lack of synergistic effect may due to suppression of PI3K by pretreatment with D. Note: This abstract was not presented at the meeting. Citation Format: Chao H. Huang, Christopher Beaudoin, Peter Van Veldhuizen, Faris Farassati. Comparison of anti-proliferation activity of BEZ 235, a multi-step inhibitor of mTOR pathway, vs. BKM120, a pan PI3K inhibitor, in lung cancer cell lines (LCCL). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4528. doi:10.1158/1538-7445.AM2014-4528