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

Atypical 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. ### Competing Interest Statement G.T. reports personal fees (advisory board, speaker`s fees) from AbbVie, Bayer, Bristol-Myers-Squibb, Medac, Novocure, travel grants from Bristol-Myers-Squibb, educational and travel grants from Novocure, research grants from Roche Diagnostics, research and travel grants from Medac. All other authors declare no competing interests. The other authors do not have any conflicts of interest to disclose.