Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Abstract

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 antitumoral 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 whether 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.

Heat stress: A risk factor for skin carcinogenesis

“…BCC incidence is on the rise, and many experts suggest that it will continue to increase in coming years (Basset-Seguin et al, 2015;Bath-Hextall et al, 2007). BCC is known to have a very low metastatic potential and mortality arising from this tumour type is approximately 0.1% (Lear et al, 2005;RoewertHuber et al, 2007).…”

Molecular Bases for Combinatorial Treatment Strategies in Patients with KRAS Mutant Lung Adenocarcinoma and Squamous Cell Lung Carcinoma

“…Hh signaling is activated following binding of Sonic Hh (Shh), Desert Hh and Indian Hh ligands to their transmembrane receptor Patched (PTCH), leading to the release of Gli transcription factors by depressing Smoothened (SMO) (Fig. 1) [95].…”

Cancer stem cells: a challenging paradigm for designing targeted drug therapies

“…Table 2 outlines current new drug discovery efforts against these key signal transduction pathways [11,47,73,[89][90][91][92][93][94].…”