Cabozantinib-Exposed Renal Cell Carcinoma Organoids Suggest Transcriptomic Associations with Treatment Resistance in Clear Cell and Nonclear Cell Tumors

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.