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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/3/958 |
| _version_ | 1797609531623079936 |
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| author | Andrew Wu Kelly A. Turner Adrian Woolfson Xiaoyan Jiang |
| author_facet | Andrew Wu Kelly A. Turner Adrian Woolfson Xiaoyan Jiang |
| author_sort | Andrew Wu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T06:02:43Z |
| format | Article |
| id | doaj.art-e1bb1e30b4974bbaacae99a64a2549f2 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T06:02:43Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-e1bb1e30b4974bbaacae99a64a2549f22023-11-17T13:16:47ZengMDPI AGPharmaceutics1999-49232023-03-0115395810.3390/pharmaceutics15030958The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid LeukemiaAndrew Wu0Kelly A. Turner1Adrian Woolfson2Xiaoyan Jiang3Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaTerry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaReplay Holdings Inc., 5555 Oberlin Drive, San Diego, CA 92121, USATerry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDespite 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.https://www.mdpi.com/1999-4923/15/3/958leukemiahematopoietic stem cellsleukemic stem cellshedgehogtargeted therapyAML |
| spellingShingle | Andrew Wu Kelly A. Turner Adrian Woolfson Xiaoyan Jiang The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia Pharmaceutics leukemia hematopoietic stem cells leukemic stem cells hedgehog targeted therapy AML |
| 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 | leukemia hematopoietic stem cells leukemic stem cells hedgehog targeted therapy AML |
| url | https://www.mdpi.com/1999-4923/15/3/958 |
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