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. 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.