Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth
Gastrointestinal stromal tumors (GISTs) comprise about 80% of mesenchymal neoplasms in the gastrointestinal tract. Although imatinib mesylate is the preferred treatment, the development of drug resistance highlights the need for novel therapeutic strategies. Recently, we have identified the micropht...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
|
| Series: | Molecular Therapy: Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329925000529 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850179489695268864 |
|---|---|
| author | Mario Guerrero Elizabeth Proaño-Pérez Eva Serrano-Candelas Alfonso García-Valverde Berenice Carrillo-Rodríguez Jordi Rosell César Serrano Margarita Martin |
| author_facet | Mario Guerrero Elizabeth Proaño-Pérez Eva Serrano-Candelas Alfonso García-Valverde Berenice Carrillo-Rodríguez Jordi Rosell César Serrano Margarita Martin |
| author_sort | Mario Guerrero |
| collection | DOAJ |
| description | Gastrointestinal stromal tumors (GISTs) comprise about 80% of mesenchymal neoplasms in the gastrointestinal tract. Although imatinib mesylate is the preferred treatment, the development of drug resistance highlights the need for novel therapeutic strategies. Recently, we have identified the microphthalmia-associated transcription factor (MITF) as a critical player in pro-survival signaling and tumor growth. This study investigates the effects of MITF inhibition using ML329, an MITF pathway inhibitor, on GIST cell viability in vitro and in NMRI-nu/nu mouse xenograft models. ML329 suppresses growth in imatinib-sensitive (GIST-T1) and -resistant (GIST 430/654) cell lines, impairs MITF targets such as BCL2 and CDK2, and induces S-G2/M cell-cycle arrest. In vivo, ML329 is well tolerated and significantly reduces tumor growth in established imatinib-sensitive and -resistant GIST models. These findings underscore the importance of MITF in GIST growth and support its inhibition as a promising therapeutic approach. |
| format | Article |
| id | doaj-art-b7e593a563254c3b9f340a628fee1ade |
| institution | OA Journals |
| issn | 2950-3299 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-b7e593a563254c3b9f340a628fee1ade2025-08-20T02:18:29ZengElsevierMolecular Therapy: Oncology2950-32992025-06-0133220098310.1016/j.omton.2025.200983Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growthMario Guerrero0Elizabeth Proaño-Pérez1Eva Serrano-Candelas2Alfonso García-Valverde3Berenice Carrillo-Rodríguez4Jordi Rosell5César Serrano6Margarita Martin7Biochemistry and Molecular Biology Unit, Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, SpainBiochemistry and Molecular Biology Unit, Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; Multidisciplinary and Translational Research in Inflammation and Immunoallergy (METRI2 A), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Facultad de Ciencias de la Salud, Universidad Técnica de Ambato, Ambato 180105, Ecuador; Nutrigenx, Universidad Técnica de Ambato, Ambato 180105, EcuadorBiochemistry and Molecular Biology Unit, Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; Multidisciplinary and Translational Research in Inflammation and Immunoallergy (METRI2 A), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainSarcoma Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 08035 Barcelona, SpainBiochemistry and Molecular Biology Unit, Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, SpainSarcoma Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 08035 Barcelona, SpainSarcoma Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, 08035 Barcelona, Spain; Department of Medical Oncology, Vall d'Hebron University Hospital, 08035 Barcelona, SpainBiochemistry and Molecular Biology Unit, Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; Multidisciplinary and Translational Research in Inflammation and Immunoallergy (METRI2 A), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Corresponding author: Margarita Martin, Biochemistry and Molecular Biology Unit, Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain.Gastrointestinal stromal tumors (GISTs) comprise about 80% of mesenchymal neoplasms in the gastrointestinal tract. Although imatinib mesylate is the preferred treatment, the development of drug resistance highlights the need for novel therapeutic strategies. Recently, we have identified the microphthalmia-associated transcription factor (MITF) as a critical player in pro-survival signaling and tumor growth. This study investigates the effects of MITF inhibition using ML329, an MITF pathway inhibitor, on GIST cell viability in vitro and in NMRI-nu/nu mouse xenograft models. ML329 suppresses growth in imatinib-sensitive (GIST-T1) and -resistant (GIST 430/654) cell lines, impairs MITF targets such as BCL2 and CDK2, and induces S-G2/M cell-cycle arrest. In vivo, ML329 is well tolerated and significantly reduces tumor growth in established imatinib-sensitive and -resistant GIST models. These findings underscore the importance of MITF in GIST growth and support its inhibition as a promising therapeutic approach.http://www.sciencedirect.com/science/article/pii/S2950329925000529MT: Regular IssueMITFcell survivalcell cyclegastrointestinal stromal tumors |
| spellingShingle | Mario Guerrero Elizabeth Proaño-Pérez Eva Serrano-Candelas Alfonso García-Valverde Berenice Carrillo-Rodríguez Jordi Rosell César Serrano Margarita Martin Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth Molecular Therapy: Oncology MT: Regular Issue MITF cell survival cell cycle gastrointestinal stromal tumors |
| title | Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth |
| title_full | Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth |
| title_fullStr | Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth |
| title_full_unstemmed | Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth |
| title_short | Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth |
| title_sort | preclinical study of microphthalmia associated transcription factor inhibitor ml329 in gastrointestinal stromal tumor growth |
| topic | MT: Regular Issue MITF cell survival cell cycle gastrointestinal stromal tumors |
| url | http://www.sciencedirect.com/science/article/pii/S2950329925000529 |
| work_keys_str_mv | AT marioguerrero preclinicalstudyofmicrophthalmiaassociatedtranscriptionfactorinhibitorml329ingastrointestinalstromaltumorgrowth AT elizabethproanoperez preclinicalstudyofmicrophthalmiaassociatedtranscriptionfactorinhibitorml329ingastrointestinalstromaltumorgrowth AT evaserranocandelas preclinicalstudyofmicrophthalmiaassociatedtranscriptionfactorinhibitorml329ingastrointestinalstromaltumorgrowth AT alfonsogarciavalverde preclinicalstudyofmicrophthalmiaassociatedtranscriptionfactorinhibitorml329ingastrointestinalstromaltumorgrowth AT berenicecarrillorodriguez preclinicalstudyofmicrophthalmiaassociatedtranscriptionfactorinhibitorml329ingastrointestinalstromaltumorgrowth AT jordirosell preclinicalstudyofmicrophthalmiaassociatedtranscriptionfactorinhibitorml329ingastrointestinalstromaltumorgrowth AT cesarserrano preclinicalstudyofmicrophthalmiaassociatedtranscriptionfactorinhibitorml329ingastrointestinalstromaltumorgrowth AT margaritamartin preclinicalstudyofmicrophthalmiaassociatedtranscriptionfactorinhibitorml329ingastrointestinalstromaltumorgrowth |