Emerging from their burrow: Hedgehog pathway inhibitors for cancer

ABSTRACT

Introduction: Cancer treatment is moving away from conventional cytotoxic drugs and towards agents that target specific proteins and mechanisms important to cancer development or survival. The Hedgehog Pathway (HhP) is a signal transduction pathway and its constitutive activation is tumorigenic in basal cell carcinoma (BCC). The HhP enables phenotypic flexibility, and channels tumor-stroma interactions. As a result, it is over-expressed in numerous cancers as well as in the tumor microenvironment and may represent a promising therapeutic target.

Areas covered: In this article, we review the rationale for targeting HhP and its role as an oncogenic driver, in tumor epithelial-to-mesenchymal transition (EMT), and in the tumor microenvironment and describe the results of preclinical and clinical studies involving HhP inhibitors.

Expert opinion: HhP activation plays an important role in both the tumor microenvironment and tumor EMT which can lead to treatment resistance for a number of different malignancies. In addition to standard use in BCC, several HhP inhibitors are in preclinical, early, and mid-stage clinical development for other solid and hematologic malignancies.

KEYWORDS:

• Epithelial-to-mesenchymal transition
• Hedgehog pathway
• tumor microenvironment
• Hedgehog inhibitors

Article highlights

• Hedgehog pathway (HhP) is critical for vertebrate embryonic patterning-development, wound repair and tissue regeneration [3,18,84].

• The canonical HhP signals through Hedgehog ligand binding to PTCH-1 leading to activation of the G-coupled protein receptor, Smoothened (SMO), which leads to GLI phosphorylation, stabilization and translocation into the nucleus as a transcription factor [4–8].

• HhP has been implicated in tumor and stromal epithelial-to-mesenchymal transition and may play a role in tumor treatment resistance, invasion, metastasis and activation of the tumor microenvironment [8,9–11,36].

• Locally advanced or metastatic basal cell carcinomas may be driven by the HhP. FDA approved HhP inhibitors are available to target oncogenically addicted BCC, and several other HhP inhibitors are under investigation in BCC and other solid tumor types [37,38,43].

• Resistance to HhP inhibitors is infrequent in BCC suggesting dependence on the HhP. A majority of the resistance mutations occur in the ligand binding pocket of SMO or impact the regulation of auto-inhibition [45–47].

• More work is needed to identify alternative mechanisms of resistance as well as inhibitors which can bypass SMO resistance mutations [25].

This box summarizes key points contained in the article.

Acknowledgments

We thank Christine Gan for her assistance with editorial and figure design.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

No funding.