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Elife
2017 ; 6
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CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in
on-going clinical trials
#MMPMID28337968
Lin A
; Giuliano CJ
; Sayles NM
; Sheltzer JM
Elife
2017[Mar]; 6
(?): ? PMID28337968
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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.
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