Targeting the Hedgehog Pathway in Rhabdomyosarcoma

Abstract

Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours-among them sarcomas-mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting.

Keywords: BOC; CDO; Desert; GAS1; Hh pathway; Indian; PTCH; SMO; STS; SUFU; Sonic; cancer; embryonic pathways; paediatric cancer; soft tissue sarcomas.

Figure 1

Inactive Hedgehog signalling. In the absence of Hh ligands, PTCH blocks the ciliary localization of SMO. The GLI transcription factors, located at the base of the primary cilium, are inhibited by the SUFU repressor complex. Then, KIF7 mediates GLI phosphorylation via PKA, CK1, and GSK3B kinases. Phosphorylated GLI1 is then ubiquitinated and totally degraded by the proteasome. However, GLI2 and GLI3 can be entirely or partially degraded. Incomplete degradation of GLI2/3 gives rise to the GLI repressor forms (GLI-R), which are translocated to the nucleus and inhibit the transcription of target genes. Image created with BioRender (BioRender.com).

Figure 2

Active Hedgehog signalling. Binding of Hh ligands (purple spheres) to PTCH causes its internalization and subsequent endosomal degradation. Then, SMO moves and accumulates in the primary cilium, where it releases the GLI transcription factors from the repressor complex. Finally, active GLI proteins (GLI-A) translocate to the nucleus, where they are able to activate the transcription of Hh target genes. Image created with BioRender (BioRender.com).

Figure 3

Aberrant mechanisms of Hh pathway activation. (a) Type I: ligand-independent constitutive activation caused by inactivating (red star) or activating (green star) mutations in different components of the pathway. (b) Type II: autoactivation of cells by high autocrine secretion of ligands. (c) Type III: paracrine Hh activation of stromal cells dependent on tumour cell ligand secretion, which, in turn, re-stimulates the tumour via pro-oncogenic Hh target secreted factors. (d) Type IIIb: reverse paracrine activation, in which stromal cells secrete Hh ligands and activate signalling in the tumour cells. Image created with BioRender.