INTRODUCTION: Basal cell carcinoma (BCC) is a malignancy that is driven by an 
activated Hedgehog (Hh) pathway. Smoothened inhibitors are a new promising 
treatment option for patients with locally advanced or metastatic BCC or basal 
cell nevus syndrome. But long-term data are still limited, the optimal treatment 
duration is not yet defined and there are already documented cases with acquired 
resistance.
AREAS COVERED: Treatment modalities with Hh inhibitors, side effects and 
potential pharmacological combination options are discussed. The current 
literature, including PubMed, Cochrane database and registered trials on 
ClinicalTrials.gov, was searched.
EXPERT OPINION: BCCs typically regress during therapy with Hh inhibitors. Muscle 
toxicity, dysgeusia and hair loss can be considered as on target adverse 
reactions. Muscle toxicity is the dose-limiting toxicity of sonidegib. It was 
not seen with vismodegib because of its high binding to plasma protein α-1-acid 
glycoprotein. Sonidegib is different and shows a clear dose-toxicity 
relationship, which allows to address the question of whether there is a dose 
dependency of regression rate, cure rate and progression-free survival. In 
addition, basic research has offered strategies to enhance efficacy by the 
combination with other molecules, such as EGFR inhibitors, MEK inhibitors or 
immunotherapy.