Genome-wide CRISPR and small-molecule screens uncover targetable dependencies in ATRT

Abstract

SummaryAtypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Concepts for molecular-driven therapies in ATRTs lag behind, mainly due to the absence of actionable genetic alterations. We performed genome-wide CRISPR/Cas9 knockout screens in six human ATRT cell lines and identified a total of 671 context-specific essential genes. Based on these genetic dependencies, we constructed a library of small-molecule inhibitors that we found to preferentially inhibit growth of ATRT cells. CDK4/6 inhibitors, among the most potent drugs in our library, are capable of inhibiting tumor growth due to mutual exclusive dependency of ATRTs on CDK4 or CDK6. These distinct dependencies drive heterogeneity in response to CDK4/6 inhibitors in ATRTs. Our approach might serve as a blueprint for fostering the identification of functionally-instructed therapeutic strategies in other incurable diseases beyond ATRT, whose genomic profiles also lack actionable alterations so far.

Utilizing preclinical models to develop targeted therapies for rare central nervous system cancers

“… 63 Merck and colleagues performed a genome-wide CRISPR/Cas9 knock-out screen in 6 human ATRT cell lines and identified 671 context-specific essential genes. 64 They used this data to rationally design a library of small molecule inhibitors and assessed cell growth in these cells, identifying CDK4/6 as a target to inhibit ATRT tumor growth. 64 Although much improved from RNAi strategies, the sgRNAs used in CRISPR screens may still result in off-target effects.…”

“… 64 They used this data to rationally design a library of small molecule inhibitors and assessed cell growth in these cells, identifying CDK4/6 as a target to inhibit ATRT tumor growth. 64 Although much improved from RNAi strategies, the sgRNAs used in CRISPR screens may still result in off-target effects. Additionally, the results of these genomic screens may identify candidates that lack specific inhibitor compounds or that are difficult to target therapeutically.…”