Abstract
More than 30 published articles have suggested that a protein kinase called MELK is an attractive therapeutic target in human cancer, but three recent reports describe compelling evidence that it is not. These reports highlight the caveats associated with some of the research tools that are commonly used to validate candidate therapeutic targets in cancer research.
Highlights
We provide some perspective on this important challenge to the field, highlighting as an example the maternal embryonic leucine zipper kinase (MELK)
We focus on three topics in particular: the use of cancer cell lines as models for target validation and therapeutic efficacy; the use of RNA interference for target validation; and the use of small-molecule pharmacologic inhibitors
In March 2017, in an article published in eLife, researchers at the Cold Spring Harbor Laboratory (CSHL) and Stony Brook University reported that they had used CRISPR/ Cas9 technology to delete MELK in 13 different human cancer cell lines of various tissue origins, and that they had observed in no significant effects on proliferation (Lin et al, 2017)
Summary
Among the key challenges faced by cancer researchers aiming to validate candidate therapeutic targets are the limitations of the model systems and reagents available to them. Most investigators rely heavily on human cancerderived cell lines and associated tumor xenografts in mice to examine the role of candidate genes and the efficacy of candidate therapeutics. Most of these cell lines have been genomically annotated, and information regarding mutations, gene expression, and other ’omic’ features is readily accessible through various public databases Importantly, these models have proved to faithfully capture at least some elements of target dependency and pharmacologic efficacy that have successfully translated to the clinic (Sharma et al, 2010).
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