Primary and secondary resistance arise via several mechanisms that activate sonic hedgehog signalling: (1) SMO mutations, either affecting the vismodegib binding pocket or allosterically, (2) mutations in genes downstream of SMO, such as GLI2 or SUFU, and/or (3) via BCC cell identity switch towards a stem cell–like transcriptional program (12, 13, 14). This evidence concerns the gene SMO and skin basal cell carcinoma.