Pooled Whole-genome CRISPR/Cas12a Loss-of-Function Screens Reveal A Novel Precision Therapeutic Opportunity for Atypical Teratoid/Rhabdoid Tumors

Abstract

Though rare, atypical teratoid/rhabdoid tumors (ATRT) remain a clinically challenging pediatric tumor and lack defined treatments. “One-size-fits-all” multimodal regimens have largely been of modest clinical benefits thereby urging the development of precision medicine for ATRT. However, the single- mutation nature of pediatric tumors like ATRT has misrepresented the potential of non-mutated pathways as viable therapeutic targets. Whole-genome CRISPR loss-of-function screens are a means of identifying genetic dependencies—an emerging concept that studies the relevance of the whole- genome towards the survival of a tumor—and therefore represent a powerful tool of identifying novel therapeutic targets for ATRT. For the first time, pooled whole-genome CRISPR/Cas12a screens were carried out on ATRT cell lines to reveal ATRT-specific biological vulnerabilities. With the increasing evidence of serum-induced phenotypic alterations among central nervous system (CNS) tumor lines, screens were also carried out in serum-free conditions for the first time. Remarkable dependency on the mitochondrial oxidative phosphorylation (OXPHOS) assembly is herein reported exclusive to ATRT, suggesting OXPHOS assembly as a potential precision therapeutic target for ATRT.