Csig-25. overcoming resistance to therapies targeting the mapk pathway in glioblastoma

Capicua (CIC) is a transcriptional repressor that inhibits expression of genes induced by receptor tyrosine kinase (RTK) activation. RTK/Ras/ERK signaling is one of the most tumorigenic pathways in cancer. In fact, the aggressive nature of the most common and lethal brain tumor, glioblastoma (GBM), has been attributed to hyperactivation of RTK. While CIC is mutated in other tumor types, we found that CIC has a tumor-suppressive function in GBM through an alternative mechanism. We show that Ras/ERK promotes degradation of CIC, resulting in de-repression of CIC targets and amplification of the tumorigenic Ras/ERK signal. Importantly, we show that sustained MEK/ERK inhibition fails to restore CIC protein levels desensitizing from upstream RTK/MEK/ERK inhibition. Our findings suggest the lack of efficacy of MEK/ERK inhibitors in GBM in the clinical context is due to the loss of CIC-mediated repression, hence exposing CIC as a potential therapeutic target in combination with MEK/ERK inhibitors. To uncover targetable pathways that stabilize CIC and sensitize towards MEK/ERK inhibitors in GBM we need to understand how CIC works and causes gene repression. We identified a novel CIC binding partner, Yin Yang 1 (YY1), a context dependent transcription factor important in GBM. We found that YY1/CIC binding co-regulates repression of genes downstream of RTK/Ras/ERK activation important in tumorigenesis. Importantly we uncovered a targetable pathway that leads to stabilization of CIC/YY1 on its target DNA which sensitizes towards MEK/ERK inhibition. These data provide insight into more effective therapeutic avenues to stabilize the CIC/YY1 co-repressor complex and re-sensitize towards RTK/Ras/MEK/ERK inhibition in GBM and likely in other tumors characterized with hyperactive Ras/ERK signaling and CIC loss.