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

Lin, A., Giuliano, C. J., Sayles, N. M., Sheltzer, J. M. (2017) CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials. Elife, 6. e24179. ISSN 2050-084x

URL: https://www.ncbi.nlm.nih.gov/pubmed/28337968
DOI: 10.7554/eLife.24179

Abstract

The Maternal Embryonic Leucine Zipper Kinase (MELK) has been reported to be a genetic dependency in several cancer types. MELK RNAi and small-molecule inhibitors of MELK block the proliferation of various cancer cell lines, and MELK knockdown has been described as particularly effective against the highly-aggressive basal/triple-negative subtype of breast cancer. Based on these preclinical results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in several clinical trials. Here, we report that mutagenizing MELK with CRISPR/Cas9 has no effect on the fitness of basal breast cancer cell lines or cell lines from six other cancer types. Cells that harbor null mutations in MELK exhibit wild-type doubling times, cytokinesis, and anchorage-independent growth. Furthermore, MELK-knockout lines remain sensitive to OTS167, suggesting that this drug blocks cell division through an off-target mechanism. In total, our results undermine the rationale for a series of current clinical trials and provide an experimental approach for the use of CRISPR/Cas9 in preclinical target validation that can be broadly applied.

Item Type: Paper
Uncontrolled Keywords: Crispr cancer biology chromosomes genes genetic dependency human mitosis protein kinase triple-negative breast cancer
Subjects: diseases & disorders > cancer
Investigative techniques and equipment > CRISPR-Cas9
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations > mutagenesis
CSHL Authors:
Communities: CSHL labs > Sheltzer lab
Depositing User: Matt Covey
Date Deposited: 30 Mar 2017 19:20
Last Modified: 30 Mar 2017 19:20
Related URLs:
URI: http://repository.cshl.edu/id/eprint/34297

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