title: Sonidegib phosphate: new approval for basal cell carcinoma.
abstract: Basal cell carcinoma (BCC), although mostly locally confined, is the most common cancer. Most BCCs harbor inactivating mutations in the membrane receptor/gene Ptch, thereby activating the Hedgehog signaling pathway (Hh) via the essential signaling molecule Smoothened (SMO). Novel small-molecule inhibitors or antagonists of SMO have shown excellent response rates in patients with locally advanced, unresectable and metastatic BCC in roughly 35-60% of patients, with disease control rates and clinical benefit being even higher. Sonidegib is the second-in-class SMO inhibitor approved for locally advanced, unresectable and metastatic BCC. Sonidegib is given once daily continuously, with specific side effects as listed in the label indication. Resistance develops over time and knowledge gleaned from other SMO inhibitors indicates that SMO mutations preventing drug binding as well as mechanisms activating the Hh pathway downstream of SMO are responsible, ultimately reactivating Hh pathway signaling. The next challenge will be to define novel salvage and SMO combination strategies for BCC and other tumors.
authors.affiliation: Mayo Clinic Division of Hematology and Oncology/Mayo Clinic Cancer Center, Scottsdale, Arizona, USA. Current affiliation: Consultant, Division of Hematology and Oncology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany. Tibes_r@ukw.de.
authors.forename: R
authors.initials: R
authors.lastname: Tibes
mesh_terms: D001713:Biphenyl Compounds / Q000627:therapeutic use*; D002280:Basal Cell Carcinoma / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D011725:Pyridines / Q000627:therapeutic use*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy*; D000072086:Smoothened Receptor
chemical_list: D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; C561435:sonidegib
keywords: Basal cell carcinoma; Hedgehog pathway; Smoothened receptor; Sonidegib