title: Molecular and cellular effects of multi-targeted cyclin-dependent kinase inhibition in myeloma: biological and clinical implications.
abstract: Cell cycle regulators, such as cyclin-dependent kinases (CDKs), are appealing targets for multiple myeloma (MM) therapy given the increased proliferative rates of tumour cells in advanced versus early stages of MM. We hypothesized that a multi-targeted CDK inhibitor with a different spectrum of activity compared to existing CDK inhibitors could trigger distinct molecular sequelae with therapeutic implications for MM. We therefore studied the small molecule heterocyclic compound NVP-LCQ195/AT9311 (LCQ195), which inhibits CDK1, CDK2 and CDK5, as well as CDK3 and CDK9. LCQ195 induced cell cycle arrest and eventual apoptotic cell death of MM cells, even at sub-μmol/l concentrations, spared non-malignant cells, and overcame the protection conferred to MM cells by stroma or cytokines of the bone marrow milieu. In MM cells, LCQ195 triggered decreased amplitude of transcriptional signatures associated with oncogenesis, drug resistance and stem cell renewal, including signatures of activation of key transcription factors for MM cells e.g. myc, HIF-1α, IRF4. Bortezomib-treated MM patients whose tumours had high baseline expression of genes suppressed by LCQ195 had significantly shorter progression-free and overall survival than those with low levels of these transcripts in their MM cells. These observations provide insight into the biological relevance of multi-targeted CDK inhibition in MM.
authors.affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute Department of Medicine, Harvard Medical School, Boston Novartis Institutes for BioMedical Research, Cambridge, MA 02115, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Jake
authors.initials: J
authors.lastname: Delmore
authors.forename: Joseph
authors.initials: J
authors.lastname: Negri
authors.forename: Leutz
authors.initials: L
authors.lastname: Buon
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jacobs
authors.forename: Jacob
authors.initials: J
authors.lastname: Laubach
authors.forename: Jana
authors.initials: J
authors.lastname: Jakubikova
authors.forename: Melissa
authors.initials: M
authors.lastname: Ooi
authors.forename: Patrick
authors.initials: P
authors.lastname: Hayden
authors.forename: Robert
authors.initials: R
authors.lastname: Schlossman
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011719:Pyrazines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000502:physiology; D016019:Survival Analysis; D014158:Transcription, Genetic; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016207:Cytokines; D004338:Drug Combinations; D011719:Pyrazines; D000069286:Bortezomib; D018844:Cyclin-Dependent Kinases