Abstract 4493: Rapamycin enhanced in vitro and in vivo activity of dexamethasone against acute lymphoblastic leukemia and lymphoma preclincal models via inhibition of p70S6 kinase activity

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Abstract Background: Glucocorticoids are an important part of therapy for lymphoid malignancies and understanding resistance mechanisms may enable designing drug combinations that will improve treatment outcome. We reported that rapamycin (RM) can enhance cytotoxicity of dexamethasone (DM) in cell culture models of lymphoid malignancies (Proc AACR 50: 4062, 2009). In the current study, we examined the mechanisms of synergy as well as in vivo activity of the DM + RM combination. Methods: Cytotoxicity of DM + RM at fixed-ratio concentrations was assessed using the DIMSCAN system in 12 acute lymphoblastic leukemia (ALL) and 3 lymphoma cell lines. Synergy was determined using the multiple drug-effect equation of Chou-Talalay with Calcusyn software. Protein was measured by immunoblotting. Phosphotransferase activity of p70 ribosomal protein S6 kinase (p70S6K) was determined using [γ-32P]ATP. In vivo drug activity was determined in NOD/SCID (ALL intravenous) and nu/nu (lymphoma, subcutaneous) mouse xenograft models. Results: DM + RM achieved cytotoxicty > 90% in 7 of 15 cell lines, and DM + RM was synergistic in 5 lines (combination index < 0.9). Among the phosphoinositide 3-kinase pathway proteins, phosphorylation of p70S6K and ribosomal protein S6 (rpS6) and also p70S6K enzyme activity was inhibited by DM + RM in those cell lines showing DM + RM synergy, but was not inhibited in lines that failed to demonstrate drug synergy. RNAi knockdown of p70S6K also significantly enhanced cytotoxicity of DM + RM in CCRF-CEM cells. In the COG-LL-317x systemic ALL and the GA-10 subcutaneous lymphoma xenograft models, DM + RM significantly (p < 0.01) extended the event-free survival (EFS) of mice compared with DM or RM as single agents. In the RS4;11 systemic ALL model, DM and DM + RM extended EFS (p < 0.01) compared with control or RM alone, although no differences in EFS was observed between DM and DM + RM. Conclusion: Our study showed that RM enhanced activity of DM in ALL and lymphoma cell lines and xenograft models and that inhibition of p70S6K activity is the molecular basis for the synergy between DM + RM in lymphoid malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4493.

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