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A Three-Way Combinatorial CRISPR Screen for Analyzing Interactions among Druggable Targets
release_hjxcaqy4cjcq7jkp2bb3silcj4
by
Peng Zhou,
Becky K.C. Chan,
Yuk Kei Wan,
Chaya T.L. Yuen,
Gigi C. G. Choi,
Xinran Li,
Cindy S.W. Tong,
Sophia S.W. Zhong,
Jieran Sun,
Yufan Bao,
Silvia Y.L. Mak,
Maggie Z.Y. Chow
(+8 others)
Abstract
We present a CRISPR-based multi-gene knockout screening system and toolkits for extensible assembly of barcoded high-order combinatorial guide RNA libraries en masse. We apply this system for systematically identifying not only pairwise but also three-way synergistic therapeutic target combinations and successfully validate double- and triple-combination regimens for suppression of cancer cell growth and protection against Parkinson's disease-associated toxicity. This system overcomes the practical challenges of experimenting on a large number of high-order genetic and drug combinations and can be applied to uncover the rare synergistic interactions between druggable targets.
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