Funktionelle Genomanalysen zur Identifizierung von Resistenzmechanismen und synthetischen Lethalitäten für CDK4/6 Inhibition in atypischen teratoid rhabdoiden Tumoren (ATRT)

01.06.2022 bis 31.05.2025

We propose to follow a functional genomics approach that will provide an unbiased, genome-wide functional analysis of tumor gene networks in distinct ATRTs. Based on our previous work using genome-scale knockout studies, CDK4/6 inhibitors are a promising targeted therapy for ATRTs, and response to CDK4/6 inhibition is largely governed by mutually exclusive dependency of ATRTs on either CDK4 or CDK6. We hypothesize that these differences in response will largely affect potential mechanisms of resistance as well as potential synthetic lethal interactions to CDK4/6 inhibitors in ATRTs, as supported by our preliminary scRNAseq data. First, we will employ genome-wide loss-of-function and gain-of-function approaches to identify genetic alterations capable to confer resistance to CDK4/6 inhibition both in CDK4- and CDK6-dependent ATRT cell lines. Second, we will focus on two partly redundant screening approaches to map synthetic lethal interactors of CDK4 and CDK6 in these distinct cell lines, revealing potential targeted therapies that could be used in combination with CDK4/6 inhibitors. Last, we will perform an in silico integration of these datasets to elucidate drug-induced vulnerabilities in ATRTs, and will go on to validate these our findings in suitable in vitro and in vivo model systems. We are confident that this project will reveal an unprecedented view of the landscape of molecular interactions for CDK4/6 inhibition in ATRTs, which has the potential to advance targeted therapies for these devastating tumors.