Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy

Abstract

The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling.

Keywords: GLI transcription factors; Hedgehog signaling; Smoothened inhibitors; cancer stem cells; drug resistance.

Figure 1

Canonical SMO-dependent HH/GLI signaling. (A) Pathway repression and GLI repressor formation in the absence of HH ligand protein. Unliganded PTCH1 prevents the ciliary translocation of the pathway effector SMO. GRP161 contributes to pathway silencing by increasing cAMP levels and PKA activity, resulting in enhanced GLI repressor formation. (B) Binding of HH ligand protein to its receptor PTCH triggers endocytic internalization of PTCH, thereby allowing ciliary entry and activation of SMO. Ciliary SMO attenuates PKA activity, thereby promoting the formation of unprocessed GLI activator forms and transcriptional activation of HH/GLI target genes, respectively.

Figure 2

Genetic and molecular mechanisms conferring resistance to SMO inhibitors. (A) Three distinct mechanisms accounting for SMO inhibitor (SMOi) resistance are displayed: (1) Mutations in SMO itself, (2) genetic loss of downstream pathway repressors such as Suppressor of Fused (SUFU), and (3) genomic amplification of pathway effectors such as GLI2. (B) SMO-independent mechanisms of oncogenic GLI regulation contributing to the development of resistance to SMO inhibitors (for details, see main text).

Figure 3

Therapeutic targeting of oncogenic HH/GLI signaling in cancer cells resistant to SMOi. Summary of targeting options to block pathways and signaling mechanisms accounting for SMO-independent GLI activation and SMOi resistance development. GF: Growth factor.