Abstract
Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities.
Highlights
Hedgehog (Hh) signaling pathway regulates multiple key developmental processes, including embryogenesis and cell proliferation, cell fate determination, and tissue patterning in vertebrates [1,2]
Data from this study indicated that activation of Hh signaling in chondrosarcoma cancer cells is type I noncanonical Hh signaling (GLI1-dependent and SMO-independent) since the Hh pathway activity can be diminished by GLI1 knockdown, but not by cyclopamine treatment
Much evidence indicates that cancer progression and relapse may not be abolished by inhibiting the Hh signaling pathway alone, and redundant bypass and crosstalk with other pathways should be taken into consideration in future therapeutics development
Summary
Hedgehog (Hh) signaling pathway regulates multiple key developmental processes, including embryogenesis and cell proliferation, cell fate determination, and tissue patterning in vertebrates [1,2]. Acquired resistance is emerging as a big challenge that compromises the clinical benefits of Hh inhibitors, and data suggested that mutations of Hh signaling components [12] and the activation of bypass signaling, such as phosphatidylinositol 3-kinase (PI3K) pathway [13], represent the potential mechanisms These findings indicated that combined inhibition of Hh signaling and other oncogenic pathways may be effective for improving the antitumor efficacy of Hh inhibitors and circumventing drug resistance. Mounting evidence has demonstrated that autophagy plays critical roles in carcinogenesis, progression, and treatment resistance of various cancers, and has emerged as a possible anticancer target for alone or in conjunction with other targets [15,16] Based on these advances, about 50 clinical trials have been proposed or are undergoing to evaluate the anticancer activity of combining autophagy modulators with chemotherapies or targeted drugs, according to the records on the ClinicalTrials.gov [17]. This review will briefly highlight the current clinical updates of Hh signaling and autophagy in cancer therapy, focus on the crosstalk between Hh pathway and autophagy, and review the preclinical attempts that combined targeting Hh signaling and autophagy in the view of potential therapeutic implications for cancer therapy
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