Guerrero Mario, Proaño-Pérez Elizabeth, Serrano-Candelas Eva, García-Valverde Alfonso, Carrillo-Rodríguez Berenice, Rosell Jordi, Serrano César, Martin Margarita
Biochemistry 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 (METRI A), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
Mol Ther Oncol. 2025 Apr 14;33(2):200983. doi: 10.1016/j.omton.2025.200983. eCollection 2025 Jun 18.
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 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. , 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.
胃肠道间质瘤（GISTs）约占胃肠道间叶性肿瘤的80%。尽管甲磺酸伊马替尼是首选治疗药物，但耐药性的出现凸显了新型治疗策略的必要性。最近，我们已确定小眼相关转录因子（MITF）是促生存信号传导和肿瘤生长的关键因子。本研究使用MITF通路抑制剂ML329研究抑制MITF对GIST细胞活力的影响以及在NMRI-nu/nu小鼠异种移植模型中的作用。ML329可抑制伊马替尼敏感（GIST-T1）和耐药（GIST 430/654）细胞系的生长，损害诸如BCL2和CDK2等MITF靶点，并诱导S-G2/M期细胞周期阻滞。此外，ML329耐受性良好，可显著降低已建立的伊马替尼敏感和耐药GIST模型中的肿瘤生长。这些发现强调了MITF在GIST生长中的重要性，并支持将抑制MITF作为一种有前景的治疗方法。
