Receptor tyrosine kinase inhibitor tivozanib regulates cell state plasticity and restores MITF dependency in BRAF wild-type melanoma

Yan-Ni Ma; Xu-Hui Ma; Mei-Ling Hao; Rui-Xin Liu; Yang Zheng; Jie Yang; Xiang-Yu Chen; Yi-Nan Chen; Sheng-Nan Zheng; Yan-Jie Zhang; Ming Lei; Min Jiang; Wei Guo; Han-Lin Zeng

doi:10.1038/s41401-025-01599-3

Receptor tyrosine kinase inhibitor tivozanib regulates cell state plasticity and restores MITF dependency in BRAF wild-type melanoma

Acta Pharmacol Sin. 2025 Jun 23. doi: 10.1038/s41401-025-01599-3. Online ahead of print.

Authors

Yan-Ni Ma^#^{1

2

3}, Xu-Hui Ma^#^{4

5

6

7}, Mei-Ling Hao^#², Rui-Xin Liu^#², Yang Zheng^#^{1

8

9

10}, Jie Yang², Xiang-Yu Chen¹¹, Yi-Nan Chen², Sheng-Nan Zheng², Yan-Jie Zhang^{2

3}, Ming Lei², Min Jiang¹², Wei Guo^{13

14

15

16}, Han-Lin Zeng^{17

18}

Affiliations

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 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. 118031@sh9hospital.org.cn.
⁵ College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200025, China. 118031@sh9hospital.org.cn.
⁶ National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai, 200011, China. 118031@sh9hospital.org.cn.
⁷ Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology; Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, 200011, China. 118031@sh9hospital.org.cn.
⁸ College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200025, China.
⁹ National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai, 200011, China.
¹⁰ Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology; Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, 200011, China.
¹¹ Department of Plastic and Cosmetic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
¹² Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China. jiangmin1023@suda.edu.cn.
¹³ Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. guoweicn@sjtu.edu.cn.
¹⁴ College of Stomatology, Shanghai Jiao Tong University, Shanghai, 200025, China. guoweicn@sjtu.edu.cn.
¹⁵ National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai, 200011, China. guoweicn@sjtu.edu.cn.
¹⁶ Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology; Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, 200011, China. guoweicn@sjtu.edu.cn.
¹⁷ Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Hanlin.Zeng@shsmu.edu.cn.
¹⁸ Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. Hanlin.Zeng@shsmu.edu.cn.

^# Contributed equally.

PMID: 40550963
DOI: 10.1038/s41401-025-01599-3

Abstract

While combination BRAF/MEK inhibition has improved survival in BRAF^V600 mutant melanoma, targeted therapies for BRAF^WT 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 BRAF^WT 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 MITF^low to MITF^high 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 BRAF^WT melanoma.

Keywords: BRAF WT melanoma; MITF; TT-012; VEGFR2; cell state plasticity; tivozanib.