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Biochemistry

Overcoming Therapeutic Resistance in Renal Cancer

Strategic Insights

— 1 min read

Research has identified a key mechanism underlying therapeutic resistance to c-Met/receptor tyrosine kinase (RTK) inhibitors in renal cancer. According to a new study from Dana-Farber Cancer Institute, the upregulation of AXL and c-Met is highly prevalent in renal cell carcinoma (RCC) cells. The study found that prolonged treatment with the c-Met/RTK inhibitor, cabozantinib (Cabo), can actually promote renal cancer cell proliferation by increasing total c-Met levels and inducing AXL-c-Met association. The researchers also discovered that inhibition or knockout of AXL can significantly overcome therapeutic resistance to c-Met inhibitors, leading to increased oxidative stress and apoptosis in tumor cells.

Key Takeaways:

  • The upregulation of AXL and c-Met is a key mechanism underlying therapeutic resistance to c-Met/RTK inhibitors in renal cancer.
  • Prolonged treatment with cabozantinib (Cabo) can increase total c-Met levels and promote renal cancer cell proliferation.
  • Inhibition or knockout of AXL can significantly overcome therapeutic resistance to c-Met inhibitors.
  • Targeting AXL and c-Met simultaneously may be a promising strategy for overcoming therapeutic resistance in renal cancer.
  • Epigenomic profiling revealed significant differences between Cabo-resistant and Cabo-sensitive RCC cells.
  • Inhibition of AXL using a potent inhibitor, TP-0903, or through genetic silencing resensitized Cabo-resistant cells to Cabo-induced cell death.
  • A combination therapy targeting both c-Met and AXL in renal cancer could be an effective approach to overcome therapeutic resistance.

Statistics:

  • 633: The issue number of the journal Cancer Letters where the research was published.
  • 217984: The article number of the journal Cancer Letters where the research was published.
  • 10 nM: The concentration of Cabo treatment that failed to inhibit HGF-c-Met phosphorylation.
  • 1 nM: The concentration of Cabo treatment that further enhanced receptor phosphorylation and downstream signaling events.
  • 2025: The year the research was conducted.

Sources:

  • Cancer Letters, 2025;633:217984.
  • NewsRx. Study Findings from Dana-Farber Cancer Institute Broaden Understanding of Kidney Cancer (Targeting AXL can effectively overcome c-Met-induced therapeutic resistance in renal cancer and promote tumor cell death through increased oxidative stress). Cancer Weekly. September 16, 2025; p 8138.

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