The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survival
Children with Group 3 medulloblastoma (G3 MB) have a very poor prognosis, and many do not survive beyond 5 years after diagnosis. A factor that may contribute to this is the lack of available targeted therapy. Expression of protein lin‐28 homolog B (LIN28B), a regulator of developmental timing, is u...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-09-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13477 |
| _version_ | 1797690647739629568 |
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| author | Shubin W. Shahab Christianna M. Roggeveen Jiarong Sun Haritha Kunhiraman Leon F. McSwain Kyle Juraschka Sachin A. Kumar Olivier Saulnier Michael D. Taylor Matthew Schniederjan Robert W. Schnepp Tobey J MacDonald Anna Marie Kenney |
| author_facet | Shubin W. Shahab Christianna M. Roggeveen Jiarong Sun Haritha Kunhiraman Leon F. McSwain Kyle Juraschka Sachin A. Kumar Olivier Saulnier Michael D. Taylor Matthew Schniederjan Robert W. Schnepp Tobey J MacDonald Anna Marie Kenney |
| author_sort | Shubin W. Shahab |
| collection | DOAJ |
| description | Children with Group 3 medulloblastoma (G3 MB) have a very poor prognosis, and many do not survive beyond 5 years after diagnosis. A factor that may contribute to this is the lack of available targeted therapy. Expression of protein lin‐28 homolog B (LIN28B), a regulator of developmental timing, is upregulated in several cancers, including G3 MB, and is associated with worse survival in this disease. Here, we investigate the role of the LIN28B pathway in G3 MB and demonstrate that the LIN28B–lethal‐7 (let‐7; a microRNA that is a tumor suppressor)–lymphokine‐activated killer T‐cell‐originated protein kinase (PBK; also known as PDZ‐binding kinase) axis promotes G3 MB proliferation. LIN28B knockdown in G3‐MB‐patient‐derived cell lines leads to a significant reduction in cell viability and proliferation in vitro and in prolonged survival of mice with orthotopic tumors. The LIN28 inhibitor N‐methyl‐N‐[3‐(3‐methyl‐1,2,4‐triazolo[4,3‐b]pyridazin‐6‐yl)phenyl]acetamide (1632) significantly reduces G3 MB cell growth and demonstrates efficacy in reducing tumor growth in mouse xenograft models. Inhibiting PBK using HI‐TOPK‐032 also results in a significant reduction in G3 MB cell viability and proliferation. Together, these results highlight a critical role for the LIN28B–let‐7–PBK pathway in G3 MB and provide preliminary preclinical results for drugs targeting this pathway. |
| first_indexed | 2024-03-12T02:02:20Z |
| format | Article |
| id | doaj.art-93a4f4cb469a4d629a58e2ccc4aa8c54 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-12T02:02:20Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-93a4f4cb469a4d629a58e2ccc4aa8c542023-09-07T10:57:03ZengWileyMolecular Oncology1574-78911878-02612023-09-011791784180210.1002/1878-0261.13477The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survivalShubin W. Shahab0Christianna M. Roggeveen1Jiarong Sun2Haritha Kunhiraman3Leon F. McSwain4Kyle Juraschka5Sachin A. Kumar6Olivier Saulnier7Michael D. Taylor8Matthew Schniederjan9Robert W. Schnepp10Tobey J MacDonald11Anna Marie Kenney12Aflac Cancer and Blood Disorders Center Children's Healthcare of Atlanta GA USADepartment of Pediatrics Emory University School of Medicine Atlanta GA USAEmory College of Arts and Sciences Emory University Atlanta GA USADepartment of Pediatrics Emory University School of Medicine Atlanta GA USADepartment of Pediatrics Emory University School of Medicine Atlanta GA USADepartment of Neurosurgery, The Hospital for Sick Children University of Toronto ON CanadaDepartment of Laboratory Medicine and Pathology University of Toronto ON CanadaThe Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children University of Toronto ON CanadaDepartment of Neurosurgery, The Hospital for Sick Children University of Toronto ON CanadaAflac Cancer and Blood Disorders Center Children's Healthcare of Atlanta GA USAAflac Cancer and Blood Disorders Center Children's Healthcare of Atlanta GA USAAflac Cancer and Blood Disorders Center Children's Healthcare of Atlanta GA USADepartment of Pediatrics Emory University School of Medicine Atlanta GA USAChildren with Group 3 medulloblastoma (G3 MB) have a very poor prognosis, and many do not survive beyond 5 years after diagnosis. A factor that may contribute to this is the lack of available targeted therapy. Expression of protein lin‐28 homolog B (LIN28B), a regulator of developmental timing, is upregulated in several cancers, including G3 MB, and is associated with worse survival in this disease. Here, we investigate the role of the LIN28B pathway in G3 MB and demonstrate that the LIN28B–lethal‐7 (let‐7; a microRNA that is a tumor suppressor)–lymphokine‐activated killer T‐cell‐originated protein kinase (PBK; also known as PDZ‐binding kinase) axis promotes G3 MB proliferation. LIN28B knockdown in G3‐MB‐patient‐derived cell lines leads to a significant reduction in cell viability and proliferation in vitro and in prolonged survival of mice with orthotopic tumors. The LIN28 inhibitor N‐methyl‐N‐[3‐(3‐methyl‐1,2,4‐triazolo[4,3‐b]pyridazin‐6‐yl)phenyl]acetamide (1632) significantly reduces G3 MB cell growth and demonstrates efficacy in reducing tumor growth in mouse xenograft models. Inhibiting PBK using HI‐TOPK‐032 also results in a significant reduction in G3 MB cell viability and proliferation. Together, these results highlight a critical role for the LIN28B–let‐7–PBK pathway in G3 MB and provide preliminary preclinical results for drugs targeting this pathway.https://doi.org/10.1002/1878-0261.134771632let‐7HI‐TOPK‐032Group 3 medulloblastomaLIN28BPBK |
| spellingShingle | Shubin W. Shahab Christianna M. Roggeveen Jiarong Sun Haritha Kunhiraman Leon F. McSwain Kyle Juraschka Sachin A. Kumar Olivier Saulnier Michael D. Taylor Matthew Schniederjan Robert W. Schnepp Tobey J MacDonald Anna Marie Kenney The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survival Molecular Oncology 1632 let‐7 HI‐TOPK‐032 Group 3 medulloblastoma LIN28B PBK |
| title | The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survival |
| title_full | The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survival |
| title_fullStr | The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survival |
| title_full_unstemmed | The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survival |
| title_short | The LIN28B–let‐7–PBK pathway is essential for group 3 medulloblastoma tumor growth and survival |
| title_sort | lin28b let 7 pbk pathway is essential for group 3 medulloblastoma tumor growth and survival |
| topic | 1632 let‐7 HI‐TOPK‐032 Group 3 medulloblastoma LIN28B PBK |
| url | https://doi.org/10.1002/1878-0261.13477 |
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