Hedgehog Pathway Inhibitors as Targeted Cancer Therapy and Strategies to Overcome Drug Resistance

Abstract

Hedgehog (Hh) signaling is a highly conserved pathway that plays a vital role during embryonic development. Recently, uncontrolled activation of this pathway has been demonstrated in various types of cancer. Therefore, Hh pathway inhibitors have emerged as an important class of anti-cancer agents. Unfortunately, however, their reputation has been tarnished by the emergence of resistance during therapy, necessitating clarification of mechanisms underlying the drug resistance. In this review, we briefly overview canonical and non-canonical Hh pathways and their inhibitors as targeted cancer therapy. In addition, we summarize the mechanisms of resistance to Smoothened (SMO) inhibitors, including point mutations of the drug binding pocket or downstream molecules of SMO, and non-canonical mechanisms to reinforce Hh pathway output. A distinct mechanism involving loss of primary cilia is also described to maintain GLI activity in resistant tumors. Finally, we address the main strategies to circumvent the drug resistance. These strategies include the development of novel and potent inhibitors targeting different components of the canonical Hh pathway or signaling molecules of the non-canonical pathway. Further studies are necessary to avoid emerging resistance to Hh inhibitors and establish an optimal customized regimen with improved therapeutic efficacy to treat various types of cancer, including basal cell carcinoma.

Keywords: basal cell carcinoma; drug resistance; hedgehog inhibitor; hedgehog signaling; smoothened inhibitor; targeted cancer therapy.

Figure 1

Canonical Hedgehog (Hh) signaling pathway in vertebrates. Shh, sonic hedgehog; Dhh, desert hedgehog; Ihh, Indian hedgehog; PTCH, Patched; SMO, Smoothened; SUFU, Suppressor of fused; GLI, glioma-associated oncogene homolog protein.

Figure 2

Non-canonical Hedgehog (Hh) signaling pathway. (A) SMO-independent GLI activation; (B) GLI-independent activation.

Figure 3

Chemical structures of the selected SMO inhibitors.

Figure 4

Locations of SMO mutations associated with drug resistance. Amino acid residues in the drug binding pocket are labeled in blue, and the residues in the non-drug binding pocket are in red. ECL, extracellular loop; ICL, intracellular loop.

Figure 5

Mechanisms of resistance to SMO inhibitors, including: (1) genetic mutations including SMO mutation, loss of SUFU, and amplification of GLI or Hh target genes; (2) activation of non-canonical Hh pathway; and (3) loss of primary cilia. The black arrows indicate the canonical Hh pathway, and the red arrow indicates the non-canonical Hh pathway.

Figure 6

Chemical structures of the selected second-generation SMO inhibitors under investigation.