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IKBKE regulates renal cell carcinoma progression and sunitinib resistance through the RRM2-AKT pathway

Shiwei Liu1,2,3, Junhong Li1,2,3, Junyu Zhang1,2,3

  • 1Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

International Journal of Biological Sciences
|December 12, 2024
PubMed

Insights

Inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE) promotes renal cell carcinoma (RCC) progression and sunitinib resistance. Targeting IKBKE may overcome drug resistance and improve sunitinib efficacy in RCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Tyrosine kinase inhibitors (TKIs) like sunitinib are key in advanced renal cell carcinoma (RCC) treatment.
  • Acquired resistance to sunitinib is a significant clinical challenge in RCC.
  • Inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE) is increasingly linked to cancer progression and drug resistance.

Purpose of the Study:

  • To investigate the role of IKBKE in RCC progression and sunitinib resistance.
  • To explore the underlying molecular mechanisms of IKBKE-mediated drug resistance.
  • To evaluate the therapeutic potential of targeting IKBKE in RCC.

Main Methods:

  • Analysis of IKBKE expression in RCC tissues and sunitinib-resistant cell lines.
  • Silencing IKBKE to assess its effects on RCC cell proliferation, cell cycle, and sunitinib sensitivity.
  • Investigating the interaction between IKBKE, ribonucleotide reductase M2 (RRM2), and the AKT signaling pathway.
  • Evaluating the efficacy of an IKBKE inhibitor (CYT387) in restoring sunitinib sensitivity.

Main Results:

  • IKBKE is upregulated in RCC tissues and sunitinib-resistant cells, correlating with advanced stage and poor prognosis.
  • IKBKE silencing suppressed RCC progression by downregulating RRM2, inducing G2/M cell cycle arrest, and enhancing sunitinib sensitivity.
  • IKBKE directly interacts with and phosphorylates RRM2, activating the AKT pathway, which drives RCC progression and sunitinib resistance.
  • The IKBKE inhibitor CYT387 restored sunitinib sensitivity by downregulating RRM2 expression.

Conclusions:

  • IKBKE inhibition restrains RCC progression and enhances sunitinib sensitivity via the RRM2-AKT pathway.
  • IKBKE represents a potential therapeutic target for overcoming sunitinib resistance in RCC.
  • Targeting IKBKE could offer a novel strategy for improving outcomes in advanced RCC patients.
Keywords:
IKBKERRM2drug resistancerenal cell carcinomasunitinib

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