The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma

• Published in: Oncogene Vol. 33; no. 3; pp. 316 - 325
• Main Authors: Munugalavadla, V, Mariathasan, S, Slaga, D, Du, C, Berry, L, Del Rosario, G, Yan, Y, Boe, M, Sun, L, Friedman, L S, Chesi, M, Leif Bergsagel, P, Ebens, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.01.2014; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67/395; 631/80/82/23; 631/92/436/2388; 692/699/67/1990/804; Animal models; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; BIM protein; Blotting, Western; c-Myc protein; Cancer; Care and treatment; Caspase-3; Catalytic subunits; Cell Biology; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Cells, Cultured; Class I Phosphatidylinositol 3-Kinases; Clinical trials; Cyclin D1; Dexamethasone; Dexamethasone - administration & dosage; Enzyme inhibitors; Female; FOXO1 protein; Genetic aspects; Human Genetics; Humans; Indazoles - administration & dosage; Indazoles - pharmacology; Inhibitory Concentration 50; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Mice; Mice, SCID; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - pathology; Myc protein; Oncology; Oncology, Experimental; original-article; Patients; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Poly(ADP-ribose) polymerase; Proto-Oncogene Proteins c-akt - metabolism; Ribose; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Testing; Thalidomide - administration & dosage; Thalidomide - analogs & derivatives; Tumor Burden - genetics; Tumor cell lines; Tumors; Xenograft Model Antitumor Assays; Xenografts; FoxO3A; multiple myeloma; PI3K; GDC-0941
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.594

The phosphatidylinositol 3′-kinase (PI3K) pathway is dysregulated in multiple myeloma (MM); we therefore tested a highly selective class I PI3K inhibitor, GDC-0941, for anti-myeloma activity. Functional and mechanistic studies were first performed in MM cell lines, then extended to primary MM patient samples cultured in vitro . GDC-0941 was then assessed as a single agent and in various combinations in myeloma tumor xenograft models. We show p110 α and β are the predominant PI3K catalytic subunits in MM and that a highly selective class I PI3K inhibitor, GDC-0941, has robust activity as a single agent to induce cell cycle arrest and apoptosis of both MM cell lines and patient myeloma cells. Mechanistic studies revealed an induction of cell cycle arrest at G 0 /G 1 , with decreased phospho-FoxO1/3a levels, decreased cyclin D1 and c-myc expression, and an increase in the cell cycle inhibitor, p27kip. Induction of apoptosis correlated with increased expression of the pro-apoptotic BH3-only protein BIM, cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP). In vitro , GDC-0941 synergized with dexamethasone (Dex) and lenalidomide (combination index values of 0.3–0.4 and 0.4–0.8, respectively); in vivo GDC-0941 has anti-myeloma activity and significantly increases the activity of the standard of care agents in several murine xenograft tumor models (additional tumor growth inhibition of 37–53% (Dex) and 22–72% (lenalidomide)). These data provide a clear therapeutic hypothesis for the inhibition of PI3K and provide a rationale for clinical development of GDC-0941 in myeloma.