ArticleJournal of experimental & clinical cancer research : CR2023
High-throughput and targeted drug screens identify pharmacological candidates against MiT-translocation renal cell carcinoma.
Article in Journal of experimental & clinical cancer research : CR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- GPNMB-directed CAR-T cell therapies for solid tumors.Nature cancer · 2026Article
- GPNMB-directed CAR T cell therapy against MiT/TFE-family fusion-driven solid tumors.Nature cancer · 2026Article
- Relapsed rhabdoid tumours and other non-nephroblastoma childhood and adolescent kidney tumours: perspectives from the HARMONICA collaboration.Nature reviews. Urology · 2026Review
- Integrated Molecular, Genomic, and Clinical Characterization of Pediatric and Adolescent Translocation Renal Cell Carcinoma: A Report from the Children's Oncology Group.Biomedicines · 2026Article
- Review
- TFE3 fusion oncoprotein condensates drive transcriptional reprogramming and cancer progression in translocation renal cell carcinoma.Cell reports · 2025Article
- Recent progress in non-clear cell renal cell carcinoma: biology and therapeutic strategies.Therapeutic advances in medical oncology · 2025Review
- Renal mass biopsy - a practical and clinicopathologically relevant approach to diagnosis.Nature reviews. Urology · 2025Review
- Management of translocation carcinomas of the kidney.Translational cancer research · 2024Review
- Article
- Design and validation of a reporter mouse to study the dynamic regulation of TFEB and TFE3 activity throughAutophagy · 2024Article
- Treatment of metastatic TFE3 microphthalmia transcription factor translocation renal cell carcinoma: a case report.Translational pediatrics · 2024Article
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Authors and funding
28 authors at 7 institutions in 3 countries.
Funding
Abstract
backgroundMiT-Renal Cell Carcinoma (RCC) is characterized by genomic translocations involving microphthalmia-associated transcription factor (MiT) family members TFE3, TFEB, or MITF. MiT-RCC represents a specific subtype of sporadic RCC that is predominantly seen in young patients and can present with heterogeneous histological features making diagnosis challenging. Moreover, the disease biology of this aggressive cancer is poorly understood and there is no accepted standard of care therapy for patients with advanced disease. Tumor-derived cell lines have been established from human TFE3-RCC providing useful models for preclinical studies.
methodsTFE3-RCC tumor derived cell lines and their tissues of origin were characterized by IHC and gene expression analyses. An unbiased high-throughput drug screen was performed to identify novel therapeutic agents for treatment of MiT-RCC. Potential therapeutic candidates were validated in in vitro and in vivo preclinical studies. Mechanistic assays were conducted to confirm the on-target effects of drugs.
resultsThe results of a high-throughput small molecule drug screen utilizing three TFE3-RCC tumor-derived cell lines identified five classes of agents with potential pharmacological efficacy, including inhibitors of phosphoinositide-3-kinase (PI3K) and mechanistic target of rapamycin (mTOR), and several additional agents, including the transcription inhibitor Mithramycin A. Upregulation of the cell surface marker GPNMB, a specific MiT transcriptional target, was confirmed in TFE3-RCC and evaluated as a therapeutic target using the GPNMB-targeted antibody-drug conjugate CDX-011. In vitro and in vivo preclinical studies demonstrated efficacy of the PI3K/mTOR inhibitor NVP-BGT226, Mithramycin A, and CDX-011 as potential therapeutic options for treating advanced MiT-RCC as single agents or in combination.
conclusionsThe results of the high-throughput drug screen and validation studies in TFE3-RCC tumor-derived cell lines have provided in vitro and in vivo preclinical data supporting the efficacy of the PI3K/mTOR inhibitor NVP-BGT226, the transcription inhibitor Mithramycin A, and GPNMB-targeted antibody-drug conjugate CDX-011 as potential therapeutic options for treating advanced MiT-RCC. The findings presented here should provide the basis for designing future clinical trials for patients with MiT-driven RCC.
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