Targeting hedgehog-driven mechanisms of drug-resistant cancers

Abstract

Due to the cellular plasticity that is inherent to cancer, the acquisition of resistance to therapy remains one of the biggest obstacles to patient care. In many patients, the surviving cancer cell subpopulation goes on to proliferate or metastasize, often as the result of dramatically altered cell signaling and transcriptional pathways. A notable example is the Hedgehog (Hh) signaling pathway, which is a driver of several cancer subtypes and aberrantly activated in a wide range of malignancies in response to therapy. This review will summarize the field's current understanding of the many roles played by Hh signaling in drug resistance and will include topics such as non-canonical activation of Gli proteins, amplification of genes which promote tolerance to chemotherapy, the use of hedgehog-targeted drugs and tool compounds, and remaining gaps in our knowledge of the transcriptional mechanisms at play.

Keywords: Gli; cancer; chemotherapy; hedgehog; resistance.

FIGURE 1

Canonical and Non-canonical Hh signaling converges on Gli proteins. Canonical (Smo-dependent) signaling is the result of a Hh ligand binding to Ptch, relieving its inhibition on Smo. Upon Smo activation, SUFU is inhibited, releasing the Gli1 and Gli2 transcription factors which then translocate into the nucleus to activate transcriptional targets. Gli2 may also be non-canonically activated by SMAD2/SMAD4 downstream of TGF-β. Created with BioRender.