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

Abstract

Cell cycle; Cell survival; Gastrointestinal stromal tumors

Ciclo celular; Supervivencia celular; Tumores del estroma gastrointestinal

Cicle cel·lular; Supervivència cel·lular; Tumors de l'estroma gastrointestinal

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.

We are indebted to the Cytomics core facility of the Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) for technical support. This study has been funded by a grant from the Spanish Ministry of Science, Innovation and Universities (MICIU) and European Regional Development Fund (ERDF)/European Social Fund “Investing in your future”: RTI2018-096915-B100 (M.M.) and PID2021-122898OB-I00 (M.M.) was funded by MICIU/AEI/10.13039/501100011033/ and by ERDF, EU. The study has also been funded by Asociación Española Contra el Cáncer (AECC CLSEN20004SERR) (C.S.) and ISCIII PI22_00720 (C.S.).