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

Abstract

Current treatment strategies for chronic lymphocytic leukemia (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. Mechanistic target of rapamycin (mTOR)-specific inhibitors have been previously assessed but their efficacy is limited due to a positive feedback loop via mTOR complex 2 (mTORC2), resulting in activation of prosurvival signaling. In this study, we show that the dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor PF-04691502 does not induce an mTORC2 positive feedback loop similar to other PI3K inhibitors but does induce substantial antitumor effects. PF-04691502 significantly reduced survival coincident with the induction of Noxa and Puma, independently of immunoglobulin heavy chain variable region mutational status, CD38, and ZAP-70 expression. PF-04691502 inhibited both anti-immunoglobulin M-induced signaling and overcame stroma-induced survival signals and migratory stimuli from CXCL12. Equivalent in vitro activity was seen in the Eμ-TCL1 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.

• Authors: Matthew D Blunt, Matthew J Carter, Marta Larrayoz, Lindsay D Smith, Maria Aguilar-Hernandez, Kerry L Cox, Thomas Tipton, Mark Reynolds, Sarah Murphy, Elizabeth Lemm, Samantha Dias, Andrew Duncombe, Jonathan C Strefford, Peter W M Johnson, Francesco Forconi, Freda K Stevenson, Graham Packham, Mark S Cragg, Andrew J Steele
• Journal: Blood (Blood) Vol. 125 Issue 26 Pg. 4032-41 (Jun 25 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25957390 (Publication Type: Journal Article)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• 2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
• Antineoplastic Agents
• Phosphoinositide-3 Kinase Inhibitors
• Pyridones
• Pyrimidines
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cells, Cultured
• Disease Models, Animal
• Female
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Phosphoinositide-3 Kinase Inhibitors
• Pyridones (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)