The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the E?-TCL1 mouse model

Abstract

Current treatment strategies for CLL involve a combination of conventional chemotherapeutics, monoclonal antibodies and targeted signaling inhibitors. However, CLL remains largely incurable with drug resistance and treatment relapse a common occurrence; leading to the search for novel treatments. mTOR specific inhibitors have been previously assessed but their efficacy is limited due to a positive feedback loop via mTORC2, resulting in activation of pro-survival signaling. Here we show that the dual PI3K/mTOR inhibitor PF-04691502 does not induce an mTORC2 positive feedback loop similar to other PI3K inhibitors but does induce substantial anti-tumor effects. PF-04691502 significantly reduced survival coincident with the induction of Noxa and Puma, independently of IGHV mutational status, CD38 and ZAP-70 expression. PF-04691502 inhibited both anti-IgM induced signaling and overcame stroma-induced survival signals as well as migratory stimuli from CXCL12. Equivalent in vitro activity was seen in the E?-TCL-1 murine model of CLL. In vivo, PF-04691502 treatment of tumor-bearing animals resulted in a transient lymphocytosis, followed by a clear reduction in tumor in the blood, bone marrow, spleen and lymph nodes. These data indicate that PF-04691502 or other dual PI3K/mTOR inhibitors in development may prove efficacious for the treatment of CLL, increasing our armamentarium to successfully manage this disease.

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