Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond

Abstract

Basal cell carcinoma (BCC) of the skin is driven by aberrant hedgehog signaling. Thus blocking this signaling pathway by small molecules such as vismodegib inhibits tumor growth. Primary cilium in the epidermal cells plays an integral role in the processing of hedgehog signaling-related proteins. Recent genomic studies point to the involvement of additional genetic mutations that might be associated with the development of BCCs, suggesting significance of other signaling pathways, such as WNT, NOTCH, mTOR, and Hippo, aside from hedgehog in the pathogenesis of this human neoplasm. Some of these pathways could be regulated by noncoding microRNA. Altered microRNA expression profile is recognized with the progression of these lesions. Stopping treatment with Smoothened (SMO) inhibitors often leads to tumor reoccurrence in the patients with basal cell nevus syndrome, who develop 10-100 of BCCs. In addition, the initial effectiveness of these SMO inhibitors is impaired due to the onset of mutations in the drug-binding domain of SMO. These data point to a need to develop strategies to overcome tumor recurrence and resistance and to enhance efficacy by developing novel single agent-based or multiple agents-based combinatorial approaches. Immunotherapy and photodynamic therapy could be additional successful approaches particularly if developed in combination with chemotherapy for inoperable and metastatic BCCs.

Keywords: BCC; hedgehog; photodynamic immunotherapy; therapeutics.

FIGURE 1

Molecular targets for therapy in the HH pathway web of collaboration. The HH pathway interacts with various other signaling networks that synergistically contribute to tumor development. PTCH is a 12-pass transmembrane receptor that generally represses SMO. HH binding to PTCH or inactivating PTCH mutations suppress this repressive response and allow for the translocation of SMO to the primary cilium to induce GLI transcription. The mTOR pathway helps release GLI from SUFU through S6K1 mediated GLI phosphorylation. The IGF/ PI3K/AKT and EGFR/MEK/ERK pathways modulate PKA-dependent phosphorylation of GLI. In the hippo pathway, MST1/2 kinases and SAV1 form a complex to phosphorylate and activate LATS1/2 and MOB1. In turn, LATS1/2 dephosphorylates YAP/TAZ, allowing the complex to translocate the nucleus and to interact with TEAD1-4 to induce the expression of genes that promote tumor progression. The aggrandizing effect of these various pathways results in BCC development, progression, and tumor resistance. Inhibiting various players within this crosstalk may lead to effective and resistance-proof treatment modalities. SMO antagonists, crosstalk pathway inhibitors, GLI antagonists, HDAC inhibitors, bromodomain inhibitors, and verteporfin target these various pathways to curb tumor development