2. Academic Validation
  3. Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth

Preclinical study of microphthalmia-associated transcription factor inhibitor ML329 in gastrointestinal stromal tumor growth

  • Mol Ther Oncol. 2025 Apr 14;33(2):200983. doi: 10.1016/j.omton.2025.200983.
Mario Guerrero 1,  Elizabeth Proaño-Pérez 1 2 3 4,  Eva Serrano-Candelas 1 2,  Alfonso García-Valverde 5,  Berenice Carrillo-Rodríguez 1,  Jordi Rosell 5,  César Serrano 5 6,  Margarita Martin 1 2
Affiliations

Affiliations

  • 1 Biochemistry and Molecular Biology Unit, Biomedicine Department, Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain.
  • 2 Multidisciplinary and Translational Research in Inflammation and Immunoallergy (METRI A), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
  • 3 Facultad de Ciencias de la Salud, Universidad Técnica de Ambato, Ambato 180105, Ecuador.
  • 4 Nutrigenx, Universidad Técnica de Ambato, Ambato 180105, Ecuador.
  • 5 Sarcoma Translational Research Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
  • 6 Department of Medical Oncology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
PMID: 40343114 DOI: 10.1016/j.omton.2025.200983
Abstract

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.

Keywords

MITF; MT: Regular Issue; cell cycle; cell survival; gastrointestinal stromal tumors.

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