ArticleCancers2022
Combination of Tipifarnib and Sunitinib Overcomes Renal Cell Carcinoma Resistance to Tyrosine Kinase Inhibitors via Tumor-Derived Exosome and T Cell Modulation.
Article in Cancers, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 30 citations in OpenAlex.
- A Review on Nanocarrier-Based Strategies for Sunitinib Delivery: Advances in Pharmacokinetic Enhancement and Targeted Theranostics.AAPS PharmSciTech · 2026Review
- Ion channel and biophysical properties of extracellular vesicles.The Journal of biological chemistry · 2026Review
- Extracellular vesicles in tumor immunity: mechanisms and novel insights.Molecular cancer · 2025Review
- Recent progress on tyrosine kinase inhibitors resistance in renal cell carcinoma: another brick in the wall?Cancer drug resistance (Alhambra, Calif.) · 2025Review
- How Advanced Are Extracellular Vesicles in Renal Cell Carcinoma? For Diagnostic and Therapeutic Frontiers.International journal of nanomedicine · 2025Review
- GHITM regulates malignant phenotype and sensitivity to PD-1 blockade of renal cancer cells via Notch signalling.Journal of cellular and molecular medicine · 2024Article
- Exosome in renal cell carcinoma progression and implications for targeted therapy.Frontiers in oncology · 2024Review
- Mediating kinase activity in Ras-mutant cancer: potential for an individualised approach?Frontiers in pharmacology · 2024Review
- Development of 6-amido-4-aminoisoindolyn-1,3-diones as p70S6K1 inhibitors and potential breast cancer therapeutics.Frontiers in molecular biosciences · 2024Article
- Exosomes in the Diagnosis and Treatment of Renal Cell Cancer.International journal of molecular sciences · 2023Review
- Molecular mechanisms of penile traction for penile rehabilitation in a bilateral cavernous nerve crush injury rat model.Translational andrology and urology · 2023Article
- Ectopic ATP synthase stimulates the secretion of extracellular vesicles in cancer cells.Communications biology · 2023Article
- Exosomes: Diagnostic and Therapeutic Implications in Cancer.Pharmaceutics · 2023Review
- Importance and implications of exosomes in nephrology and urology.Pflugers Archiv : European journal of physiology · 2023Review
- Small Extracellular Vesicles as a New Class of Medicines.Pharmaceutics · 2023Review
- Advances in the research of exosomes in renal cell carcinoma: from mechanisms to applications.Frontiers in immunology · 2023Review
- Extracellular vesicles in renal cell carcinoma: challenges and opportunities coexist.Frontiers in immunology · 2023Review
- Pharmacological therapy of metabolic dysfunction-associated steatotic liver disease-driven hepatocellular carcinoma.Frontiers in pharmacology · 2023Review
- Article
- Exosome-Mediated Response to Cancer Therapy: Modulation of Epigenetic Machinery.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundTyrosine kinase inhibitors (TKI) were initially demonstrated as an efficacious treatment for renal cell carcinoma (RCC). However, after a median treatment length of 14 months, a vast majority of patients develop resistance. This study analyzed a combination therapy of tipifarnib (Tipi) + sunitinib that targeted exosome-conferred drug resistance.
methods786-O, 786-O-SR (sunitinib resistant), A498, A498-SR, Caki-2, Caki-2-SR, and 293T cells were cultured. Exosomes were collected using differential ultracentrifugation. Cell proliferation, Jurkat T cell immune assay, and immunoblot analysis were used for downstream analysis.
resultsSR exosomes treatment displayed a cytotoxic effect on immune cells. This cytotoxic effect was associated with increased expression of PD-L1 on SR exosomes when compared to sunitinib-sensitive (SS) exosomes. Additionally, Tipi treatment downregulated PD-L1 expression on exosomes derived from SR cell lines. Tipi's ability to downregulate PD-L1 in exosomes has a significant application within patients. Exosomes collected from patients with RCC showed increased PD-L1 expression over subjects without RCC. Next, exosome concentrations were then compared after Tipi treatment, with all SS cell lines displaying an even greater reduction. On immunoblot assay, 293T cells showed a dose-dependent increase in Alix with no change in either nSMase or Rab27a. Conversely, all the SS and SR cell lines displayed a decrease in all three markers. After a cell proliferation employed a 48-h treatment on all SS and SR cell lines, the drug combination displayed synergistic ability to decrease tumor growth.
conclusionsTipifarnib attenuates both the exosome endosomal sorting complex required for endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways, thereby blocking exosome biogenesis and secretion as well as downregulating PD-L1 on SS and SR cells.
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