Vismodegib is indicated for locally advanced basal cell carcinoma (la BBC), although some instances of the drug’s intrinsic resistance (IR) have been observed. For a study, researchers wanted to understand how often IR to vismodegib occurs in la BBC and what genomic mechanisms are involved. In a study of 148 la BBC patients, vismodegib was evaluated. A subset of 5 intrinsically resistant BCC (IR-BCC) was analyzed for comprehensive genomic and transcriptomic analysis. Furthermore, 6.1% of la BBC was identified as IR-BCC in the study. IR was associated with prior chemotherapy treatment. The genetic events that were previously linked with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC patients. However, IR-BCCs were unusual in that their polyploid genomes had been considerably rearranged. In IR-BCC, functional analyses revealed hyperactivation of the HIPPO-YAP and WNT pathways in both RNA and protein formats. The cell proliferation rate was increased after YAP1 overexpression in the in vitro assay on the BCC cell line. In la BBC, vismodegib to ibrutinib was a rare occurrence. TIR-BCC malignancies were frequently Hh pathway resistant changes, yet they were further characterized by HIPPO-YAP and WNT hyperactivation.