Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models

We report a novel resistance mechanism to CDK4/6 inhibition in Hedgehog-associated medulloblastoma where cell models and mouse models demonstrate that prolonged inhibition of CDK4/6 inhibits ribosome biogenesis, activates the unfolded protein response, and increases the amount of Smoothened-activating lipids. This RNA-Sequencing dataset represents genomically-engineered mouse medulloblastoma models that either have wild-type Cdk6 or genomic knockout of Cdk6. We find that tumors that grew despite genetic loss of Cdk6 have suppresed ribosome biogenesis. Overall design: comparison of genetically engeinereed mouse medulloblastomas that have intact Cdk6 or genetic deleiton of Cdk6. Sequencing was performed on a Illumina HiSeq 4000 with 50bp single-end reads with at least 37 million reads per sample. Differential expression analysis was performed with DESeq2.