Aurora kinase and FGFR3 inhibition results in significant apoptosis in molecular subgroups of multiple myeloma

// Utkarsh Painuly 1, 2, * , Vijay Ramakrishnan 1, * , Teresa Kimlinger 1 , Linda Wellik 1 , Jessica Haug 1 , Wilson Gonsalves 1 , Lintao Bi 1, 3 , Zhongxia Huang 1 , S. Vincent Rajkumar 1 and Shaji Kumar 1 1 Division of Hematology, Mayo Clinic, Rochester, MN, USA 2 4th Department of Internal Medicine–Hematology University Hospital Hradec Kralove and Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic 3 The Department of Hematology and Oncology, China-Japan Union Hospital attached to JiLin University, Changchun, Jilin, China * These authors contributed equally to this work Correspondence to: Shaji Kumar, email: kumar.shaji@mayo.edu Keywords: multiple myeloma; FGFR3; Aurora kinase; apoptosis; proliferation Received: February 15, 2016      Accepted: September 15, 2018      Published: October 02, 2018 ABSTRACT Aberrant expression of proteins involved in cell division is a constant feature in multiple myeloma (MM), especially in high-risk disease. Increasingly, therapy of myeloma is moving towards individualization based on underlying genetic abnormalities. Aurora kinases are important mediators of cell cycle and are up regulated in MM. Functional loss of Aurora kinases results in genetic instability and dysregulated division leading to cellular aneuploidy and growth arrest. We investigated the role of Aurora kinase inhibition in MM, using a small molecule inhibitor A1014907. Low nanomolar A1014907 concentrations induced aneuploidy in MM cell lines independent of underlying cytogenetic abnormalities by inhibiting Aurora Kinases. However, A1014907 induced more pronounced and dose dependent apoptosis in cell lines with t(4;14) translocation. Translocation t(4;14) is observed in about 15% of patients with MM leading to constitutive activation of FGFR3 in two-thirds of these patients. Further investigation of the mechanism of action of A1014907 revealed potent FGFR3 pathway inhibition only in the sensitive cell lines. Thus, our results show that aurora kinase inhibition causes cell cycle arrest and aneuploidy with minimal apoptosis whereas inhibiting both aurora kinase and FGFR3 activity induced potent apoptosis in MM cells. These results support clinical evaluation of A1014907 in MM patients with t(4;14) translocation and/or FGFR3 expression.