Lin, A., Giuliano, C. J., Sayles, N. M., Sheltzer, J. M. (March 2017) CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials. Elife, 6. e24179. ISSN 2050-084x
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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 Cancer Center Program > Cancer Genetics CSHL labs > Sheltzer lab Northwell Health CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matt Covey |
| Date: | 24 March 2017 |
| Date Deposited: | 30 Mar 2017 19:20 |
| Last Modified: | 05 Nov 2020 19:29 |
| PMCID: | PMC5365317 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/34297 |
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