title: The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma.
abstract: 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 G0/G1, 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.
authors: Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA.
authors: V
authors: V
authors: Munugalavadla
authors: Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA.
authors: S
authors: S
authors: Mariathasan
authors: Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA.
authors: D
authors: D
authors: Slaga
authors: Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA.
authors: C
authors: C
authors: Du
authors: Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA.
authors: L
authors: L
authors: Berry
authors: Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA.
authors: G
authors: G
authors: Del Rosario
authors: Department of Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA.
authors: Y
authors: Y
authors: Yan
authors: Department of Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA.
authors: M
authors: M
authors: Boe
authors: Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA.
authors: L
authors: L
authors: Sun
authors: Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA.
authors: L S
authors: LS
authors: Friedman
authors: Department of Medicine, Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA.
authors: M
authors: M
authors: Chesi
authors: Department of Medicine, Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA.
authors: P
authors: P
authors: Leif Bergsagel
authors: Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA.
authors: A
authors: A
authors: Ebens
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D000077269:Lenalidomide; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D003907:Dexamethasone; D007191:Indazoles; D000077269:Lenalidomide; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; D013792:Thalidomide; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C484760:PIK3CA protein, human; C497132:PIK3CB protein, human