Basal cell carcinoma (BCC) is the most commonly diagnosed cancer. While most BCCs are amenable to surgery, some tumors can reach a more advanced stage or metastasize, and become ineligible for surgical resection or radiotherapy. Abnormal activation of the Hedgehog (Hh) pathway is a key driver in BCC pathophysiology. Consequently, inhibitors of the Hh pathway have been developed. Molecules that inhibit the receptor protein Smoothened (SMO) are the most advanced in clinical development. Vismodegib is the first-in-class SMO inhibitor and has been approved in a number of countries for the treatment of metastatic or locally advanced BCC. Several molecules have demonstrated anti-tumoral activity, but treatment may be limited in duration by a number of side effects and it is not yet established whether these agents are truly curative or if continued treatment will be required. Resistance to SMO inhibition has been reported in the clinic for which incidence and mechanisms must be elucidated to inform future therapeutic strategies. Intermittent dosing regimens to improve tolerability as well as neoadjuvant use of Hh pathway inhibitors are currently under investigation. Here we review the most recent outcomes obtained with Hh inhibitors under clinical investigation in BCC.
- Received August 27, 2014.
- Revision received December 1, 2014.
- Accepted December 1, 2014.
- Copyright © 2015, American Association for Cancer Research.