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The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia

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 home...

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Autores principales: Wu, Andrew, Turner, Kelly A., Woolfson, Adrian, Jiang, Xiaoyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053130/
https://www.ncbi.nlm.nih.gov/pubmed/36986819
http://dx.doi.org/10.3390/pharmaceutics15030958
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author Wu, Andrew
Turner, Kelly A.
Woolfson, Adrian
Jiang, Xiaoyan
author_facet Wu, Andrew
Turner, Kelly A.
Woolfson, Adrian
Jiang, Xiaoyan
author_sort Wu, Andrew
collection PubMed
description 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.
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spelling pubmed-100531302023-03-30 The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia Wu, Andrew Turner, Kelly A. Woolfson, Adrian Jiang, Xiaoyan Pharmaceutics Review 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. MDPI 2023-03-16 /pmc/articles/PMC10053130/ /pubmed/36986819 http://dx.doi.org/10.3390/pharmaceutics15030958 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Wu, Andrew
Turner, Kelly A.
Woolfson, Adrian
Jiang, Xiaoyan
The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia
title The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia
title_full The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia
title_fullStr The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia
title_full_unstemmed The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia
title_short The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia
title_sort hedgehog pathway as a therapeutic target in chronic myeloid leukemia
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053130/
https://www.ncbi.nlm.nih.gov/pubmed/36986819
http://dx.doi.org/10.3390/pharmaceutics15030958
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