Kinome expression profiling to target new therapeutic avenues in multiple myeloma

Multiple myeloma account for approximately 10% of hematological malignancies and is the second most common hematological disorder. Kinases inhibitors are widely used and demonstrated their efficiency for the treatment of cancers. Here, in order to identify kinases with potential therapeutic interest in multiple myeloma, we investigated the prognostic impact of the kinome expression profile in large cohorts of patients. We identified 36 kinome-related genes significantly linked with a prognostic value in multiple myeloma, and built a Kinome index based on their expression. Kinome index is linked to prognosis, proliferation, differentiation, and relapse in multiple myeloma. We then tested inhibitors targeting seven of the identified protein kinases (PBK, SRPK1, CDC7-DBF4, MELK, CHK1, PLK4, MPS1/TTK) in human myeloma cell lines. All tested inhibitors significantly reduced viability of myeloma cell lines, and we confirmed the potential clinical interest of three of them on primary myeloma cells from patients. In addition, we demonstrated their ability to potentialize the toxicity of conventional treatments, including Melphalan and Lenalidomide. This highlights their potential benefic effect in myeloma therapy. Three kinases inhibitors (CHK1i, MELKi and PBKi) overcome resistance to Lenalidomide, while CHK1, PBK and DBF4 inhibitors re-sensitized Melphalan resistant cell line to this conventional therapeutic agent. Altogether, we demonstrate that kinase inhibitors could be of therapeutic interest especially in high-risk myeloma patients defined by the Kinome Index. CHEK1, MELK, PLK4, SRPK1, CDC7-DBF4, MPS1/TTK and PBK inhibitors could represent new treatment options alone or in combination with Melphalan or IMiDs for refractory/relapsing myeloma patients.