STEM-18. DISTINCT BUT PREDICTABLE MECHANISMS DRIVE GENETIC VS. EPIGENETIC RESISTANCE TO TARGETED THERAPY

Abstract Emergence of therapy resistance greatly reduces long-term utility of effective targeted therapies, including SMO/SHH pathway inhibitors. SHH signaling is activated in ~25% of human medulloblastomas (MB) and FDA approved SMOi (to treat basal cell carcinoma (BCC)) are currently in clinical trials for MBs and acute myeloid leukemia (AML). Accumulating clinical experience suggests that a significant number of BCC patients treated with SMOi develop acquired resistance over time and some show de novo resistance. A similar pattern is observed in MB patients, indicating the need to elucidate resistance mechanisms, particularly those driving de novo vs. acquired resistance, and develop new strategies to overcome both de novo and acquired resistance to SMOi. We report that we have discovered a novel, epigenetic mechanism of therapy resistance to SMOi that underlie de novo resistance. Using two different mouse models of SHH MB, we tested our original hypothesis that the selective pressure on cancer stem cells (CSCs), but not bulk tumor cells, will determine the resistance mechanism at the molecular level. We show that acquired mutations in the SHH pathway genes (previously reported mechanism of resistance) occur only in tumors that contain CSCs that depend on the SHH pathway. In tumors where only the bulk tumor cells, but not CSCs, depend on SHH signaling, no acquired mutations in the SHH pathway genes are detected. Instead, in these tumors, epigenetic reprogramming through selective degradation of specific histone modifiers results in global changes in the epigenetic cell state and gene expression patterns. Importantly, we can predict the mechanism of resistance in individual tumors prior to treatment based on CSC phenotypes. Finally, we also report biomarkers that can be used to identify tumors with CSCs that are independent of SHH pathway, which can be exploited to design anticipatory combination therapies in the future.