The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia.
AML
CML
combination therapy
hedgehog
hematopoietic stem cells
leukemia
leukemic stem cells
signal transduction pathways
small molecule inhibitors
targeted therapy
Journal
Pharmaceutics
ISSN: 1999-4923
Titre abrégé: Pharmaceutics
Pays: Switzerland
ID NLM: 101534003
Informations de publication
Date de publication:
16 Mar 2023
16 Mar 2023
Historique:
received:
03
02
2023
revised:
08
03
2023
accepted:
13
03
2023
medline:
30
3
2023
entrez:
29
3
2023
pubmed:
30
3
2023
Statut:
epublish
Résumé
Despite the development of therapeutic agents that selectively target cancer cells, relapse driven by acquired drug resistance and resulting treatment failure remains a significant issue. The highly conserved Hedgehog (HH) signaling pathway performs multiple roles in both development and tissue homeostasis, and its aberrant regulation is known to drive the pathogenesis of numerous human malignancies. However, the role of HH signaling in mediating disease progression and drug resistance remains unclear. This is especially true for myeloid malignancies. The HH pathway, and in particular the protein Smoothened (SMO), has been shown to be essential for regulating stem cell fate in chronic myeloid leukemia (CML). Evidence suggests that HH pathway activity is critical for maintaining the drug-resistant properties and survival of CML leukemic stem cells (LSCs), and that dual inhibition of BCR-ABL1 and SMO may comprise an effective therapeutic strategy for the eradication of these cells in patients. This review will explore the evolutionary origins of HH signaling, highlighting its roles in development and disease, which are mediated by canonical and non-canonical HH signaling. Development of small molecule inhibitors of HH signaling and clinical trials using these inhibitors as therapeutic agents in cancer and their potential resistance mechanisms, are also discussed, with a focus on CML.
Identifiants
pubmed: 36986819
pii: pharmaceutics15030958
doi: 10.3390/pharmaceutics15030958
pmc: PMC10053130
pii:
doi:
Types de publication
Journal Article
Review
Langues
eng
Subventions
Organisme : CIHR
ID : CIHR
Pays : Canada
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