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

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 Eμ-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 PF04691502 or other dual PI3K/mTOR inhibitors in development may prove efficacious for the treatment of CLL, increasing our armamentarium to successfully manage this disease. For personal use only. on November 22, 2015. by guest www.bloodjournal.org From