Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia

Abstract

Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

“…4,5 Maternal embryonic leucine zipper kinase (MELK) is a member of the AMP protein kinase (AMPK) family of serine/threonine kinases, and MELK activates multiple cellular pathways that drive oncogenic growth. [8][9][10][11][12][13] It has been shown that MELK is overexpressed in multiple human tumours, including the following: melanoma, 8 diffuse intrinsic pontine glioma (DIPG), 14 breast cancer, 6,15 gastric cancer, 16 high-grade prostate cancer, 17 hepatocellular carcinoma, 18 kidney cancer, 19 small lung cancer, 20 myeloma, 21 acute myeloid leukaemia (AML) 22 and chronic lymphocytic leukaemia (CLL). [8][9][10][11][12][13] It has been shown that MELK is overexpressed in multiple human tumours, including the following: melanoma, 8 diffuse intrinsic pontine glioma (DIPG), 14 breast cancer, 6,15 gastric cancer, 16 high-grade prostate cancer, 17 hepatocellular carcinoma, 18 kidney cancer, 19 small lung cancer, 20 myeloma, 21 acute myeloid leukaemia (AML) 22 and chronic lymphocytic leukaemia (CLL).…”

“…23 High levels of MELK are correlated with clinically aggressive disease and poor survival. 19,[22][23][24][25] A number of studies have shown that MELK inhibition also increases sensitivity to radiation and chemotherapy in pre-clinical adult cancer models, suggesting that combination treatments may also be effective strategies. 19,[22][23][24][25] A number of studies have shown that MELK inhibition also increases sensitivity to radiation and chemotherapy in pre-clinical adult cancer models, suggesting that combination treatments may also be effective strategies.…”

CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials

“…However, several discrepancies exist in the literature on MELK. For instance, various publications disagree over the cell cycle stage affected by MELK inhibition (Du et al, 2014; Kig et al, 2013; Alachkar et al, 2014; Wang et al, 2014; Beke et al, 2015), while other publications disagree over whether receptor-positive breast cancer cell lines are sensitive (Lin et al, 2007; Beke et al, 2015; Chung et al, 2012) or resistant (Wang et al, 2014) to MELK inhibition. To unambiguously determine the effects of MELK loss in cancer cell lines, we applied CRISPR/Cas9 to generate frameshift mutations in the MELK coding sequence.…”

“…MELK is also over-expressed in most types of solid tumors, including breast, colon, liver, lung, melanoma, and ovarian cancer (Gray et al, 2005). Furthermore, many publications have reported that knocking down MELK using RNAi inhibited the proliferation of cell lines derived from these cancer types (Gray et al, 2005; Lin et al, 2007; Kuner et al, 2013; Du et al, 2014; Kig et al, 2013; Speers et al, 2016; Alachkar et al, 2014; Marie et al, 2008; Nakano et al, 2008; Hebbard et al., 2010; Wang et al, 2014; Choi et al, 2011; Xia et al, 2016; Gu et al, 2013). In particular, MELK has been identified as a key driver of basal-type breast cancer, suggesting a novel therapeutic approach to treat this disease (Wang et al, 2014).…”

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

“…Both genes have previously been shown to be upregulated in cancer. 42,43 Furthermore, FLT1 has been shown play a role in the proliferation of tumor cells, 44 and suppression of MELK expression by siRNA has been shown to inhibit the growth of cancer cells. Therefore, the aberrant expression of these genes due to DNA methylation may provide a survival advantage to malignant cells and play a role in pediatric ALL.…”