Receptor tyrosine kinase inhibitor tivozanib regulates cell state plasticity and restores MITF dependency in BRAF wild-type melanoma
Yan-ni Ma1,2,3,
Xu-hui Ma1,4,5,6,7,8,9,
Mei-ling Hao2,
Rui-xin Liu2,
Yang Zheng1,4,5,6,7,8,9,
Jie Yang2,
Xiang-yu Chen10,
Yi-nan Chen2,
Sheng-nan Zheng2,
Yan-jie Zhang2,3,
Ming Lei2,
Min Jiang11,
Wei Guo1,4,5,6,7,8,9,
Han-lin Zeng2,3
1 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
2 Shanghai Institute of Precision Medicine, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
3 Department of Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
4 College of Stomatology, Shanghai Jiao Tong University, Shanghai 200025, China
5 National Center for Stomatology
6 National Clinical Research Center for Oral Diseases, Shanghai 200011, China
7 Shanghai Key Laboratory of Stomatology
8 Shanghai Research Institute of Stomatology
9 Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai 200011, China
10 Department of Plastic and Cosmetic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
11 Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
Correspondence to: Xu-hui Ma: 118031@sh9hospital.org.cn, Min Jiang: jiangmin1023@suda.edu.cn, Wei Guo: guoweicn@sjtu.edu.cn, Han-lin Zeng: Hanlin.Zeng@shsmu.edu.cn,
DOI: 10.1038/s41401-025-01599-3
Received: 14 January 2025
Accepted: 22 May 2025
Advance online: 23 June 2025
Abstract
While combination BRAF/MEK inhibition has improved survival in BRAFV600 mutant melanoma, targeted therapies for BRAFWT melanoma remain limited. Microphthalmia transcription factor (MITF), a lineage-specific transcription factor that regulates melanocyte proliferation and melanin synthesis, represents a promising melanoma-specific drug target. In this study, we evaluated TT-012, a recently identified MITF dimerization specific inhibitor, and surprisingly found that most BRAFWT melanoma lines were resistant to TT-012 due to low MITF transcriptional activity and reduced dependency on MITF for proliferation. High-throughput drug screen identified tivozanib, an FDA-approved drug targeting VEGFR and other receptor tyrosine kinases (RTKs), which sensitized cells to TT-012. Mechanistically, tivozanib induced cell state transition from MITFlow to MITFhigh state via VEGFR2 inhibition followed by NF-κB pathway activation, restoring MITF transcriptional activity and growth dependency. The combination of tivozanib and TT-012 synergistically inhibited melanoma growth both in vitro and in vivo, underscoring its potential as a novel therapeutic strategy for BRAFWT melanoma.
