Abstract
The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (<xref ref-type="bibr" rid="bib34">Lin et al., 2017</xref>). Here, we generate several additional knockout clones of MELK and demonstrate that across cancer types, cells lacking MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. By combining our MELK-knockout clones with a recently described, highly specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies.
Highlights
Cancer cells require the expression of certain genes, called “addictions” or “genetic dependencies”, that encode proteins necessary for tumor growth
In contrast to these results, we recently reported that triple-negative breast cancer cells harboring CRISPR/Cas9-induced loss of function mutations in Maternal Embryonic Leucine Zipper Kinase (MELK) proliferate at wild-type levels in vitro [15]
Western blot analysis confirmed that full-length mouse or human MELK was overexpressed in all six cell lines that we generated relative to the level of MELK in vectortransduced control cell lines (Figure 1A,D)
Summary
Cancer cells require the expression of certain genes, called “addictions” or “genetic dependencies”, that encode proteins necessary for tumor growth. Silencing the expression of these genes or blocking the activity of the proteins that they encode can trigger cell death and durable tumor regression [1]. The Maternal Embryonic Leucine Zipper Kinase (MELK) has been implicated as a cancer dependency and putative drug target in multiple cancer types, including melanoma, colorectal cancer, and triple-negative breast cancer [2,3,4,5,6]. On the basis of these pre-clinical results, several companies have developed small-molecule MELK inhibitors, and one MELK inhibitor (OTS167) is currently being tested in multiple clinical trials [14]
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