The utility of hedgehog signaling pathway inhibition for cancer

Abstract

The Hedgehog (Hh) signaling pathway has been implicated in tumor initiation and metastasis across different malignancies. Major mechanisms by which the Hh pathway is aberrantly activated can be attributed to mutations of members of Hh pathway or excessive/inappropriate expression of Hh pathway ligands. The Hh signaling pathway also affects the regulation of cancer stem cells, leading to their capabilities in tumor formation, disease progression, and metastasis. Preliminary results of early phase clinical trials of Hh inhibitors administered as monotherapy demonstrated promising results in patients with basal cell carcinoma and medulloblastoma, but clinically meaningful anticancer efficacy across other tumor types seems to be lacking. Additionally, cases of resistance have been already observed. Mutations of SMO, activation of Hh pathway components downstream to SMO, and upregulation of alternative signaling pathways are possible mechanisms of resistance development. Determination of effective Hh inhibitor-based combination regimens and development of correlative biomarkers relevant to this pathway should remain as clear priorities for future research.

Figure 1.

Hedgehog signalling. (A) Hedgehog ligands (Hhl) bind to PTCH1 and unrepress SMO with activation of GLI and target genes. (B) The tumor produces Hhl and stimulates itself. (C) Tumor cells produce Hhl and activate signaling in nonmalignant cells. In turn, other signaling pathways are activated and stimulate tumor growth (arrow). (D) Stromal cells produce the Hhl required for tumor growth/survival.