pnd-1186 and Multiple-Myeloma

Topics: Aminopyridines; Benzamides; Drug Resistance, Neoplasm; Focal Adhesion Kinase 1; Focal Adhesion Kinase 2; Humans; Hypoxia; Multiple Myeloma; Proteasome Inhibitors; Pyrazines; Sulfonamides; Tumor Cells, Cultured

Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared with healthy individuals. By using loss-of-function approaches, we found that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell proliferation, cell-cycle progression, and adhesion ability in vitro. In turn, overexpression of Pyk2 promoted the malignant phenotype, substantiated by enhanced tumor growth and reduced survival. Mechanistically, inhibition of Pyk2 reduced activation of Wnt/β-catenin signaling by destabilizing β-catenin, leading to downregulation of c-Myc and Cyclin D1. Furthermore, treatment of MM cells with the FAK/Pyk2 inhibitor VS-4718 effectively inhibited MM cell growth both in vitro and in vivo. Collectively, our findings describe the tumor-promoting role of Pyk2 in MM, thus providing molecular evidence for a novel tyrosine kinase inhibitor as a new therapeutic option in MM.

Topics: Aminopyridines; Animals; beta Catenin; Cell Adhesion; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Disease Progression; Female; Focal Adhesion Kinase 2; Gene Expression Regulation, Enzymologic; Green Fluorescent Proteins; HEK293 Cells; Humans; Immunoblotting; Luminescent Measurements; Mice, SCID; Multiple Myeloma; Protein Kinase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Survival Analysis; Tumor Burden; Wnt Signaling Pathway; Xenograft Model Antitumor Assays