NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Metastatic clear cell renal cell carcinoma (ccRCC) has a poor prognosis, with limited treatment options beyond anti-PD-1 immunotherapy.
• Despite advances, a significant unmet need exists for novel therapeutic strategies in ccRCC, particularly for patients with advanced disease.

Purpose of the Study:

• To identify novel molecular predictors of ccRCC progression and therapeutic targets.
• To investigate the role of the mitotic regulator NDC80 in ccRCC pathogenesis and its potential as a therapeutic target.

Main Methods:

• Integrated network analysis to identify ccRCC progression predictors.
• Functional studies assessing NDC80's impact on cell cycle, glycolysis, and mitochondrial respiration.
• Bioinformatic analysis to correlate NDC80 expression with treatment response.
• In vitro and in vivo validation of mitotic kinase inhibitors in ccRCC models.

Main Results:

• NDC80 was identified as a predictor of ccRCC progression, with its overexpression promoting cell cycle progression, glycolysis, and mitochondrial respiration.
• NDC80-high ccRCCs exhibit high immune infiltration but are resistant to immune checkpoint blockade.
• Bioinformatics and experimental validation indicated that NDC80-high ccRCCs are sensitive to PLK1 and AURK kinase inhibitors.

Conclusions:

• NDC80 is a crucial driver of ccRCC malignancy and a marker for poor response to immunotherapy.
• Inhibitors targeting mitotic kinases PLK1 and AURK represent a promising therapeutic strategy for NDC80-high ccRCC.
• NDC80 status can guide treatment decisions for difficult-to-treat ccRCC patients.