Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches

Simple Summary: Chemotherapy is the mainstay of cancer treatment; however, its use is limited due to the emergence of chemotherapeutic drug resistance in cancers. An essential developmental pathway, namely Hedgehog (Hh), has recently emerged as a major modulator of cancer progression and, more importantly, chemoresistance. Preclinical results have implicated Hh signaling as a promising therapeutic strategy for the chemosensitization of Hh-causing cancers. Despite this, most Hh-targeting inhibitors still remain in preclinical stages, and their use in conjunction with chemotherapy in clinical settings is still underdeveloped. To solve this, a better understanding and identification of the relevant mechanisms regulated by Hh signaling to promote chemoresistance in different cancers are necessary to develop more effective treatment strategies. In this review, we outlined the mechanisms by which Hh induces chemoresistance in cancer. Additionally, current therapeutic strategies utilizing a combination of both Hh inhibitors and chemotherapeutics for overcoming chemoresistance in preclinical and clinical settings are also presented. Insight into cancer signaling pathways is vital in the development of new cancer treatments to improve treatment efficacy. A relatively new but essential developmental signaling pathway, namely Hedgehog (Hh), has recently emerged as a major mediator of cancer progression and chemoresistance. The evolutionary conserved Hh signaling pathway requires an in-depth understanding of the paradigm of Hh signaling transduction, which is fundamental to provide the necessary means for the design of novel tools for treating cancer related to aberrant Hh signaling. This review will focus substantially on the canonical Hh signaling and the treatment strategies employed in different studies, with special emphasis on the molecular mechanisms and combination treatment in regard to Hh inhibitors and chemotherapeutics. We discuss our views based on Hh signaling's role in regulating DNA repair machinery, autophagy, tumor microenvironment, drug inactivation, transporters, epithelial-to-mesenchymal transition, and cancer stem cells to promote chemoresistance. The understanding of this Achilles' Heel in cancer may improve the therapeutic outcome for cancer therapy.

Automated summary

The Hedgehog (Hh) signaling pathway plays a crucial role in cancer treatment, particularly in chemotherapy resistance. Understanding the mechanisms regulated by Hh signaling is essential for developing more effective treatment strategies in cancer therapy.