BCCs are invasive epithelial tumors that originate from activating mutations in the Hedgehog (Hh) pathway. Despite the critical nature of Hh signaling in cancer initiation and progression, the signaling pathways that cooperate with Hh to facilitate its proliferative effects remain poorly understood. Hh pathway activation begins when Hh ligand binds and inhibits transmembrane receptor Patched1, allowing signal transducer Smoothened (Smo) to activate Gli transcription factors and amplify expression of Hh target genes. Smo inhibitors have recently gained FDA approval for treatment of advanced or metastatic BCC and exhibit potent tumor regression. While these inhibitors are effective in nave tumors, aggressive tumors tend to develop early resistance to the drug, illustrating the need to understand BCC resistance mechanisms. To understand the genetics of BCC drug resistance we have performed whole exome and RNA sequencing of resistant versus sensitive human BCC tumors. We found that mutations in genes that comprise the primary cilium, a microtubule based sensory organelle found on most vertebrate cells, were significantly enriched in drug resistant BCCs. Furthermore, microscopic analysis reveals a dramatic decrease in the percentage of ciliated cells in resistant versus sensitive human BCC samples. The goal of my research is to determine the functional consequence of the mutations within the ciliome and loss of primary cilia on Hh pathway activation and drug resistant BCC growth. To further characterize the cilia defect on the cellular and genomic level I will perform targeted resequencing of the ciliome in additional matched sensitive and normal BCC patient samples. This will identify cilia mutations that are acquired as the tumors evolve to evade Smo inhibition. Additionally I will investigate how the loss of function of genes that are mutated in resistant BCCs affects Hh pathway signaling and determine the mechanism by which loss of cilia contributes to growth of BCCs downstream of Smo inhibition. The results of this study will reveal novel mechanisms of acquired Hh inhibitor resistance, which will be critical for generating therapeutics effective at treating drug resistant Hh-dependent cancers.
Basal Cell Carcinoma (BCC) is the most prevalent cancer worldwide and is driven by activating mutations in the Hedgehog (Hh) pathway. Recently developed therapeutics that target the Hh pathway are effective against nave BCCs but approximately 20% of treated tumors develop drug resistance. My proposed work will reveal how altered regulation of the primary cilium, a sensory organelle, mediates the Hh pathway and contributes to mechanisms of BCC drug resistance.
