Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma
CHALLENGE - Basal cell carcinomas (BCCs) are characterized by loss-of-function mutations in the tumor suppressor gene, PTCH1, which normally functions by repressing the activity of the Smoothened (SMO) receptor. Inactivating PTCH1 mutations result in constitutive Hedgehog pathway activity through uncontrolled SMO signaling. Generally, patients with genetic defects in the Hh pathway are targeted with vismodegib, a novel SMO inhibitor which results in tumor regression. This report reveals that a secondary mutation in SMO has occured in patients following relapse on vismodegib to date.
SOLUTION - The molecular mechanisms of resistance to vismodegib in two BCC cases are presented. A PTCH1 and SMO mutational analysis and in silico experimentation were carried out. In silico analysis demonstrated that SMOG497W undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network
BENEFITS - In silico experiments involved an extensively validated procedure based on the Molecular Mechanics/PoissoneBoltzmann Surface Area (MM-PBSA) methodology. The entire MM-PBSA computational procedure was optimized by integrating AMBER 12 in the optimization software modeFRONTIER.