Targeting KIT With Antibody-Drug Conjugates in Chromophobe Renal Cell Carcinoma

Chromophobe renal cell carcinoma (ChRCC) is the third most common type of RCC. There are no proven therapies for patients with metastatic ChRCC, with a median survival of 27 months. KIT (CD117) is a membrane-associated tyrosine kinase receptor. Antibody-drug conjugates (ADC) targeting KIT were previously found to be safe and effective in preclinical models of KIT-positive cancers but have not been tested in ChRCC.

In The Cancer Genome Atlas, KIT mRNA expression is higher in ChRCC than any other tumor type with the mean expression 12 times higher than matched normal kidney. Of the 15 metastatic ChRCC specimens stained for KIT at our institution, 87% were positive. In single-cell RNA sequencing data, KIT and SCF, the KIT ligand, are co-expressed in ChRCC tumor cells. We found that KIT mRNA expression is significantly higher in ChRCC-derived cells compared to clear cell renal cell carcinoma (ccRCC)-derived cells and normal kidney cells. Western blot analysis confirmed KIT expression in 5 ChRCC cell lines. Despite high KIT expression, knockdown of KIT or treatment with KIT targeting tyrosine kinase inhibitors did not decrease ChRCC cell proliferation. LOP628, a KIT ADC, decreased the viability of the ChRCC-derived cells by ∼60% with no effect on ccRCC cells.

Together, these data demonstrate that KIT is a viable therapeutic target for antibody-drug conjugates in ChRCC, providing a foundation for further investigation into KIT-targeted therapies.