Overcoming the resistance mechanisms of Smoothened inhibitors

•The possible mechanism of acquired resistance to Smo inhibitors was reviewed.•Development of second-generation inhibitors is critical to combat Smo resistance.•Gli inhibition could benefit to patients with Smo-inhibitor resistant tumors.•The Hh-associated oncogenic signaling pathways represent potential therapeutic targets. Smoothened (Smo), the main transducer of the Hedgehog (Hh) signaling pathway, is a promising target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been associated with mutation-related drug resistance. In this review, we outline the resistance mechanisms of Smo inhibitors and point the way for future endeavors. We focus in particular on the development of second-generation Smo inhibitors based on co-crystal structures, inhibition of downstream components, and the regulation of other interacting pathways or mediators that could compensate for the inhibitory activity of upstream inhibitors.