A functional genomics approach to define resistance mechanisms and synthetic lethal interactions of CDK4/6 inhibition in atypical teratoid rhabdoid tumors (ATRT)

• Applicant: Dr. Daniel Merk
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496706655

Brain tumors are the leading cause of cancer-related death in children and adolescents. Embryonal brain tumors are the most common high-grade neoplasms in children under the age of 5, and include three major tumor entities: medulloblastoma (MB), atypical teratoid rhabdoid tumors (ATRT), and embryonal tumors with multilayered rosettes (ETMR). In spite of a better understanding of the molecular biology of these tumors in recent years, survival estimates for these tumors stay relatively low, with current standard of care inflicting a substantial degree of long-term side effects. Thus, there is desperate need for novel, targeted therapies for these tumor entities. Recently, similarly to MB, molecular subgroups for ATRTs have been described, but the impact of this finding on potential targeted therapies remains unclear.Using a combination of genome-wide CRISPR/Cas9 knockout and small molecule drug screening, we have previously generated a map of dependencies for ATRTs, implicating CDK4/6 inhibitors as one of the most promising candidates for targeted therapy in ATRTs. Of note, ATRTs show distinct patterns of CDK4 and CDK6 genetic dependencies and underlying transcriptional profiles which as independent of molecular subgroups, and these differences predict distinct responses to CDK4/6 inhibition in ATRT tumor cells. We here propose to use genome-wide CRISPR/Cas9 functional genomic screens in distinct modalities to uncover resistance mechanisms as well as genetic interactors for CDK4/6 inhibition in ATRTs, thereby providing the basis for precision medicine for this tumor entity. First, we will use both loss-of-function and gain-of-function genome-scale perturbation screens to uncover genetic alterations capable of conferring resistance to CDK4/6 inhibition. Second, we will perform CRISPR/Cas9 screens to identify genetic alterations that synergize with CDK4/6 inhibition in ATRTs, thus representing synthetic lethal interactions that might be efficacious in combination therapies. Last, we will integrate our findings from screening approaches to elucidate drug-induced vulnerabilities in ATRTs and validate those in suitable model systems. Specifically, we will focus on distinct molecular responses and potential combinatorial therapies that might be correlated with distinct dependencies in the CDK4/6 axis in ATRTs. We are confident that this project will provide novel insights into the molecular biology of ATRTs that will significantly advance the prediction of novel, targeted therapies for this type of embryonal brain tumor.

• DFG Programme: Research Grants