Maternal embryonic leucine zipper kinase is a novel target for proliferation-associated high-risk myeloma

Abstract

Treatment of high-risk patients is a major challenge in multiple myeloma. This is especially true for patients assigned to the gene expression profiling-defined proliferation subgroup. Although recent efforts have identified some key players of proliferative myeloma, genetic interactions and players that can be targeted with clinically effective drugs have to be identified in order to overcome the poor prognosis of these patients. We therefore examined maternal embryonic leucine zipper kinase (MELK) for its implications in hyper-proliferative myeloma and analyzed the activity of the MELK inhibitor OTSSP167 both in vitro and in vivo. MELK was found to be significantly overexpressed in the proliferative subgroup of myeloma. This finding translated into poor overall survival in patients with high vs. low MELK expression. Enrichment analysis of upregulated genes in myeloma cells of MELKhigh patients confirmed the strong implications in myeloma cell proliferation. Targeting MELK with OTSSP167 impaired the growth and survival of myeloma cells, thereby affecting central survival factors such as MCL-1 and IRF4. This activity was also observed in the 5TGM.1 murine model of myeloma. OTSSP167 reduced bone marrow infiltration and serum paraprotein levels in a dose-dependent manner. In addition, we revealed a strong link between MELK and other proliferation-associated high-risk genes (PLK-1, EZH2, FOXM1, DEPDC1) and MELK inhibition also impaired the expression of those genes. We therefore conclude that MELK is an essential component of a proliferative gene signature and that pharmacological inhibition of MELK represents an attractive novel approach to overcome the poor prognosis of high-risk patients with a proliferative expression pattern.

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

“…As described above, increased MELK expression was already reported in a variety of solid (breast, prostate, etc.) and hematological cancers (leukemia and multiple myeloma), and has been associated with a worse clinical outcome for these patients 6,[14][15][16][17][18] . Consistent with these reports, MELK gene expression was also found significantly elevated in all DLBCL and MCL subtypes compared with their normal counterparts.…”

“…Targeting MELK in different cancer cell types, using either siRNA knockdown or pharmacological inhibition, resulted in an impaired tumor growth by inducing apoptosis and/or decreasing cell proliferation both in vitro and in vivo 11,15,[17][18][19][20][21][22][23][24] . Several agents were already used to target MELK, such as MELK-T1 38 , MELK-8a 39 , MELK-IN-1 40 , and OTSSP167 41 .…”

“…To further improve the anti-lymphoma activity of OTSSP167, in vitro combination studies were performed. Previously, studies in multiple myeloma and breast cancer demonstrated that combining OTSSP167 with standard-ofcare agents (including lenalidomide, pomalidomide, and bortezomib) could increase the anti-cancer effect of the standard-of-care agent 18,53 . A promising novel agent in clinical development in DLBCL and MCL is the selective Bcl-2 inhibitor venetoclax (also known as ABT-199).…”

“…In addition, enhancer of zeste homolog 2 (EZH2), c-Jun, p53, apoptosis signal-regulating kinase 1 (ASK1), DEPDC1, and SOX2 are also targets of MELK 5,7,13 . Several studies observed high MELK levels in different types of cancer and MELK overexpression is often associated with a poor prognosis 6,7,[14][15][16][17][18] . Moreover, knockdown studies resulted in decreased survival of cancer cells 19,20 .…”

“…The implication of MELK in tumor growth makes it an attractive therapeutic target for cancer therapy 7 . OTSSP167 is a potent MELK inhibitor and was shown to impair cancer growth in leukemia, myeloma, small cell lung cancer, neuroblastoma, prostate cancer, and kidney cancer cells 15,18,[21][22][23][24] . As such, OTSSP167 is currently tested in different clinical trials in patients with solid tumors and refractory and relapsed leukemia 25 .…”