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AltmetricGiuliano, C. J., Lin, A., Smith, J. C., Palladino, A. C., Sheltzer, J. M. (February 2018) MELK expression correlates with tumor mitotic activity but is not required for cancer growth. Elife, 7. ISSN 2050-084x
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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.
| Item Type: | Paper |
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| Uncontrolled Keywords: | CRISPR/Cas9 biomarkers cancer biology cell cycle drug targets human mitotic kinase with Google Inc. The author has no financial interests to declare. |
| Subjects: | diseases & disorders > cancer Investigative techniques and equipment > CRISPR-Cas9 organs, tissues, organelles, cell types and functions > organelles, types and functions > mitosis |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cancer Genetics CSHL labs > Sheltzer lab Northwell Health |
| Depositing User: | Matt Covey |
| Date: | 8 February 2018 |
| Date Deposited: | 20 Feb 2018 20:39 |
| Last Modified: | 11 Jan 2019 20:04 |
| PMCID: | PMC5805410 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36079 |
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