Hedgehog signals are transduced through
Patched receptors to the Smoothened (SMO)-SUFU-GLI and SMO-Gi-RhoA signaling cascades. MTOR-S6K1 and
MEK-ERK signals are also transduced to GLI activators through post-translational modifications. The GLI transcription network up-regulates target genes, such as BCL2, FOXA2, FOXE1, FOXF1, FOXL1, FOXM1, GLI1, HHIP, PTCH1 and WNT2B, in a cellular context-dependent manner. Aberrant Hedgehog signaling in
tumor cells leads to self-renewal, survival, proliferation and invasion. Paracrine Hedgehog signaling in the tumor microenvironment (TME), which harbors cancer-associated fibroblasts, leads to angiogenesis,
fibrosis, immune evasion and
neuropathic pain. Hedgehog-related genetic alterations occur frequently in
basal cell carcinoma (BCC) (85%) and Sonic Hedgehog (SHH)-subgroup
medulloblastoma (87%) and less frequently in
breast cancer,
colorectal cancer,
gastric cancer,
pancreatic cancer,
non-small-cell lung cancer (NSCLC) and
ovarian cancer. Among investigational SMO inhibitors,
vismodegib and
sonidegib are approved for the treatment of patients with BCC, and
glasdegib is approved for the treatment of patients with
acute myeloid leukemia (AML). Resistance to SMO inhibitors is caused by acquired SMO mutations, SUFU deletions, GLI2 amplification, other by-passing mechanisms of GLI activation and WNT/β-
catenin signaling activation. GLI-
DNA-interaction inhibitors (
glabrescione B and
GANT61), GLI2 destabilizers (
arsenic trioxide and
pirfenidone) and a GLI-deacetylation inhibitor (4SC-202) were shown to block GLI-dependent transcription and
tumorigenesis in preclinical studies. By contrast, SMO inhibitors can remodel the immunosuppressive TME that is dominated by M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells and regulatory T cells, and thus, a Phase I/II clinical trial of the
immune checkpoint inhibitor pembrolizumab with or without
vismodegib in BCC patients is ongoing.