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.

Identification of new hypoxia‐regulated epithelial‐mesenchymal transition marker genes labeled by H3K4 acetylation

“…GLI1 has been also suggested to be a prognostic biomarker and therapeutic target for an aggressive subclass of hepatocellular carcinoma patients . New classes of inhibitors against SMO/GLI1 are undergoing development in order to treat tumors containing aberrant activity of these two molecules …”

“…49 New classes of inhibitors against SMO/GLI1 are undergoing development in order to treat tumors containing aberrant activity of these two molecules. 50 It is interesting that BMI1 is among the new hypoxia-induced EMT marker genes (Supporting Information Figure S2). BMI1 has been extensively studied and characterized as a cancer stem cell factor that contributes to EMT and chemoresistance and may serve as a therapeutic target.…”

Oncogenic GLI1 and STAT1/3 activation drives immunosuppressive tryptophan/kynurenine metabolism via synergistic induction of IDO1 in skin cancer cells

“…Uncontrolled activation of the Hedgehog (HH)/glioma-associated oncogene homolog (GLI) pathway can cause and promote the development and progression of several malignant diseases, of which basal cell carcinoma (BCC) with 3-4 million new cases per year in the US alone representing the most common cancer in the Western world [2]. During the past years, several small molecule inhibitors selectively targeting HH/GLI signaling were approved for the treatment of HH-driven cancers including advanced and metastatic basal cell carcinoma (BCC) and acute myeloid leukemia (reviewed in [3][4][5][6][7][8]). Despite these impressive advancements, frequent and rapid development of drug resistance, insufficient response and efficacy and severe adverse effects pose major challenges, calling for improved therapeutic strategies [9][10][11][12].…”

“…In brief, HH/GLI signaling is initiated via binding of secreted HH protein to its receptor Patched (PTCH), which -via endocytotic removal of the HH-PTCH complex -allows the essential pathway effector Smoothened (SMO), a seven-pass transmembrane protein, to translocate into the primary cilium. There, active SMO initiates a GLI-STAT driven immunosuppression via IDO1 induction 4 signaling cascade that ultimately results in the formation of high-levels of active GLI transcription factors such as GLI1/2 driving HH target gene expression and tumor development (for detailed reviews see [7,[13][14][15][16][17]).…”

Production of BBF2H7‐derived small peptide fragments via endoplasmic reticulum stress‐dependent regulated intramembrane proteolysis

“…19,22 The pathway plays crucial roles in chondrogenesis by activation of extracellular matrix protein secretion. Nevertheless, multiple genetic and molecular mechanisms resulting in resistance to existing Hh pathway-targeting drugs pose major limitations to anti-Hh therapies 30 . 23 Hh signaling modulates diverse events including cell proliferation.…”