title: Novel inhibition of PIM2 kinase has significant anti-tumor efficacy in multiple myeloma.
abstract: The PIM kinase family (PIM1, 2 and 3) have a central role in integrating growth and survival signals, and are expressed in a wide range of solid and hematological malignancies. We now confirm that PIM2 is overexpressed in multiple myeloma (MM) patients, and within MM group it is overexpressed in the high-risk MF subset (activation of proto-oncogenes MAF/MAFB). This is consistent with our finding of PIM2's role in key signaling pathways (IL-6, CD28 activation) that confer chemotherapy resistance in MM cells. These studies have identified a novel PIM2-selective non-ATP competitive inhibitor (JP11646) that has a 4 to 760-fold greater suppression of MM proliferation and viability than ATP-competitive PIM inhibitors. This increased efficacy is due not only to the inhibition of PIM2 kinase activity, but also to a novel mechanism involving specific downregulation of PIM2 mRNA and protein expression not seen with the ATP competitive inhibitors. Treatment with JP11646 in xenogeneic myeloma murine models demonstrated significant reduction in tumor burden and increased median survival. Altogether our findings suggest the existence of previously unrecognized feedback loop(s) where PIM2 kinase activity regulates PIM2 gene expression in malignant cells, and that JP11646 represents a novel class of PIM2 inhibitors that interdicts this feedback.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Nair
authors.affiliation: Jasco Pharmaceuticals, Woburn, MA, USA.|Boston Biomedical, Inc., Cambridge, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Caserta
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Belko
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Howell
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Fetterly
authors.affiliation: Jasco Pharmaceuticals, Woburn, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Baldino
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy*; D016328:NF-kappa B / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases