title: High throughput chemical library screening identifies a novel p110-δ inhibitor that potentiates the anti-myeloma effect of bortezomib.
abstract: Multiple myeloma (MM) remains an incurable plasma cell malignancy and drug resistance persists as the major cause of treatment failure leading to fatal outcomes. The phosphatidyl-inositol-3-kinase (PI3K) pathway is constitutively hyperactivated in MM to promote disease progression and drug resistance. While inhibiting PI3K induces apoptosis in MM and is predicted to increase tumor susceptibility to anticancer therapy, early-generation pan-PI3K inhibitors display poor clinical efficacy as well as intolerable side effects. Here, we found that PI3K activity is significantly upregulated in MM cell lines and patient tumor cells resistant to bortezomib and that the majority of PI3K activity in MM cells is dependent upon the p110-δ isoform. Genetic or pharmacologic inhibition of p110-δ substantially reduced myeloma viability and enhanced cellular sensitivity to bortezomib. Chemical library screens then identified a novel compound, DT97, that potently inhibited p110-δ kinase activity and induced apoptosis in MM cells. DT97 was evaluated in the NCI-60 panel of human cancer cell types and anticancer activity was greatest against MM, leukemia and lymphoma cells. Co-treatment with DT97 and bortezomib synergistically induced apoptosis in MM patient cells and overcame bortezomib-resistance. Although bone marrow stromal cells (BMSCs) promote MM growth, the pro-survival effects of BMSCs were significantly reduced by DT97 treatment. Co-treatment with bortezomib and DT97 reduced the growth of myeloma xenotransplants in murine models and prolonged host survival. Taken together, the results provide the basis for further clinical evaluation of p110-δ inhibitors, as monotherapy or in synergistic combinations, for the benefit of MM patients.
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, OH, USA.|Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Malek
authors.affiliation: Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|University of Cincinnati Cancer Institute, Cincinnati, OH, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Driscoll
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D000069286:Bortezomib; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human
keywords: bortezomib resistance; multiple myeloma; p110-delta; phosphatidylinositol 3-kinase; proteasome