摘要：The Hedgehog (Hh) signal transduction pathway has been discovered as a central regulator of embryonic development, tissue maintenance and repair [1]. Moreover, several recent evidences have highlighted its key function in tumorigenesis [2]. In some familial cancers, such as basal cell carcinoma and medulloblastoma, Hh pathway activation represents the initial tumorigenic event, whereas in other human malignancies, including gastrointestinal, lung, brain, breast and prostate cancers, deregulation of Hh signaling occurs during tumor progression and participates in tumor maintenance. Clinical trials using molecular inhibitors targeting Hh pathway components, in particular the Smo receptor, have often yielded limited clinical benefits unless they are used for the treatment of tumors harboring defined genetic mutations inactivating tumor suppressors (e.g. Ptch receptor) or activating oncogenes (e.g. Smo receptor, Gli transcription factor, Shh ligand) within the Hh pathway. In these specific cases, promising results led to FDA approval of Vismodegig (GDC0449, Genentech), a Smo inhibitor, in the treatment of basal cell carcinoma and medulloblastoma [3]. Notwithstanding, several clinical studies using the same compound in tumors exhibiting Hh overactivity without identified Hh mutations have resulted in discouraging outcome and discontinuation of the trials because of lack of objective response [2]. These unexpected results have been related to drug resistance due to the presence of activating mutations or genetic alterations driving Hh signaling bypassing Smo function. These evidences emphasize the need for further characterization of Hh signaling in tumorigenesis and for a more precise identification of the interaction between Hh and other signaling pathways involved in tumor development and response to therapy.
