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

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.