Related Experiment Video
Updated: May 14, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Cabozantinib-Exposed Renal Cell Carcinoma Organoids Suggest Transcriptomic Associations with Treatment Resistance in
Wesley H Chou1, Nicholas H Chakiryan1,2,3, George V Thomas1,4
1Department of Urology, Oregon Health & Science University, Portland, Oregon.
Abstract:
While vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a mainstay of treatment for advanced renal cell carcinoma (RCC), mechanisms of resistance to VEGF-TKIs remain under ongoing investigation. To assess transcriptomic changes in clear-cell RCC (ccRCC) and non-ccRCC exposed to a VEGF-TKI, we analyzed differential single-cell gene expression in RCC tumor-organoids exposed to cabozantinib versus control solvent. In ccRCC organoid cells, LRRC75A was notably highly associated with cabozantinib exposure (log2 fold-change 2.18, detected proportion 0.52 vs. 0.23, false-detection rate adjusted p<0.001). Importantly, our findings were independently validated in a recent study of advanced ccRCC patients treated with cabozantinib, which demonstrated that higher LRRC75A expression was significantly associated with decreased tumor response and less robust reduction of VEGF expression. LRRC75A has been shown to mediate VEGF secretion in a separate study and may potentiate compensatory angiogenesis after cabozantinib exposure. Gene expression scores were then developed based on transcriptomic changes associated with cabozantinib exposure and applied to stage IV patients in several independent cohorts. Higher scores were significant predictors of worse overall survival in TCGA non-RCC patients and worse progression-free survival in JAVELIN Renal 101 ccRCC patients. Overall, this experiment represents an incremental step in a larger effort to elucidate resistance mechanisms to VEGF-TKIs.
Insights
Leucine-rich repeat-containing protein 75A (LRRC75A) may drive resistance to vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) in advanced renal cell carcinoma (RCC). Higher LRRC75A expression correlates with poorer treatment response and survival outcomes in RCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are standard treatments for advanced renal cell carcinoma (RCC).
- Mechanisms of resistance to VEGF-TKIs in RCC are not fully understood, necessitating further investigation into molecular drivers.
- Understanding resistance pathways is crucial for improving therapeutic strategies in advanced RCC.
Purpose of the Study:
- To identify transcriptomic alterations associated with VEGF-TKI exposure in clear-cell RCC (ccRCC) and non-ccRCC.
- To investigate the role of specific genes, such as LRRC75A, in mediating resistance to cabozantinib, a VEGF-TKI.
- To validate findings in patient cohorts and assess their predictive value for treatment response and survival.
Main Methods:
- Differential single-cell gene expression analysis of RCC tumor-organoids exposed to cabozantinib versus control.
- Validation of gene expression findings in independent cohorts of advanced ccRCC patients treated with cabozantinib.
- Development and application of gene expression scores to predict survival outcomes in stage IV RCC patients.
Main Results:
- LRRC75A expression was significantly upregulated in ccRCC organoid cells upon cabozantinib exposure.
- Higher LRRC75A expression in patients correlated with decreased tumor response and reduced VEGF suppression.
- Elevated gene expression scores, reflecting cabozantinib-induced transcriptomic changes, predicted worse overall and progression-free survival.
Conclusions:
- LRRC75A may play a critical role in mediating resistance to VEGF-TKIs by promoting compensatory angiogenesis.
- LRRC75A expression serves as a potential biomarker for predicting treatment response and prognosis in advanced RCC.
- These findings contribute to a deeper understanding of VEGF-TKI resistance mechanisms in RCC.
