Sonic Hedgehog Self-Renewal Inhibitors

The sonic hedgehog pathway is a third highly conserved pathway involved in tissue growth and repair as well as PaCSC self-renewal. In pancreatic adenocarcinoma, KRAS promotes sonic hedgehog expression via the inflammatory transcription factor NF-kB (Gu et al. 2016). The sonic hedgehog protein inhibits the receptor patched, which releases its inhibition of the protein smoothened. Smoothened leads to the activation and nuclear localization of GLI transcription factors, which regulates expression of target genes. An appealing target for this pathway is smoothened, and inhibitors BMS-833923 and PF-0444913 serve as effective treatments for pancreatic adenocarcinoma (Jia et al. 2019). These two inhibitors work most efficiently in combination with gemcitabine, but also have shown beneficial effects on their own (Jia et al. 2019). The researchers plan to incorporate these two smoothened inhibitors, BMS-833923 and PF-0444913, into their treatment as well to block the self-renewal of PaCSCs.