Advanced treatment for basal cell carcinomas

Abstract

Basal cell carcinomas (BCCs) are very common epithelial cancers that depend on the Hedgehog pathway for tumor growth. Traditional therapies such as surgical excision are effective for most patients with sporadic BCC; however, better treatment options are needed for cosmetically sensitive or advanced and metastatic BCC. The first approved Hedgehog antagonist targeting the membrane receptor Smoothened, vismodegib, shows remarkable effectiveness on both syndromic and nonsyndromic BCCs. However, drug-resistant tumors frequently develop, illustrating the need for the development of next-generation Hedgehog antagonists targeting pathway components downstream from Smoothened. In this article, we will summarize available BCC treatment options and discuss the development of next-generation antagonists.

Figure 1.

HH pathway activation. (A) In the absence of HH ligand, ciliary PTCH1 inhibits SMO activity and ciliary localization. SUFU prevents GLI nuclear localization and target gene induction. (B) HH ligand binds and induces PTCH1 translocation from the cilia, allowing active SMO to enter the cilia and suppress SUFU function, allowing active GLI to enter the nucleus and induce target genes.

Figure 2.

Model of tumor heterogeneity. A normal cell (green) can convert to a tumor cell (purple) by acquiring an HH pathway mutation. As the tumor cell divides, clonal populations (blue) can gain secondary mutations that promote drug resistance. When SMO antagonist is applied, tumors with no resistant clones will shrink, whereas tumors with resistant clones will continue to grow.

Figure 3.

Resistance pathways in HH-dependent cancers. One of the most common resistance pathways is Smo mutation in the ligand binding pocket or the carboxyl terminus. Activation of GLI downstream from SMO also appears to be a frequent resistance pathway that can bypass SMO inhibition. GLI is directly activated by atypical protein kinase C ι/λ (aPKC), which requires activation by PDK1. S6 kinase 1 (S6K1) prevents SUFU inhibition of GLI, and is activated by the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. PI3K can promote PDK1 activation and PDK1 can promote mTOR and S6K1 activation, but whether these molecular events can cause resistance in HH-dependent cancers remains to be determined. PI3K can also promote resistance in a GLI-independent manner.