Basal cell carcinoma (BCC) is primarily driven by the Sonic Hedgehog (Hh) pathway. Eighty-five percent of the BCCs harbors mutations in Hh pathway genes. In basal cell carcinoma, activating mutations in SMO are associated with sensitivity to Hedgehog pathway inhibitors.

Some studies have demonstrated activity of sonic hedgehog pathway inhibitors in a subset of medulloblastomas harboring alterations in this pathway.

This gene is a known cancer gene.

This gene is a known cancer gene.

Smoothened (SMO) is a co-receptor involved in the Hedgehog (Hh) signaling. Constitutive or aberrant activation of the Hh pathway leading to tumorigenesis is seen in many cancers with SMO activating mutations identified in basal cell carcinoma and medulloblastoma. Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been recently developed for cancer treatment. Germline or somatic SMO mutations have not been previously characterized in NSCLC; however, in a recent report a germline SMO P641A mutation in a patient with refractory NSCLC responded to vismodegib therapy for several months. The functional effect of SMO V404M is conflicting as it demonstrated activity similar to the normal protein in culture in one study, but resulted in near complete loss of Hh pathway signaling in another study, and therefore, its effect on SMO protein function is unknown. Clinical correlation is recommended.