Abstract 2119: Targeting KIT in chromophobe renal cell carcinoma

Background: Chromophobe renal cell carcinoma (ChRCC) arises from the specialized intercalated cells of the distal nephron. There are no proven therapies for patients with metastatic ChRCC. In the metastatic setting median survival is estimated to be 27 months. KIT (CD117) is a membrane-associated tyrosine kinase receptor. Binding of the ligand stem cell factor (SCF) to KIT results in kinase activation and internalization. Antibody-drug conjugates (ADC) targeting KIT were previously found to be effective in preclinical models and safe in primates, but have not been tested in ChRCC. Results: In The Cancer Genome Atlas (TCGA), KIT (CD117) mRNA expression is higher in ChRCC than any other tumor type with the mean expression 12 times higher than matched normal kidney. In contrast, in clear cell RCC (ccRCC), KIT (CD117) is 5 times lower than matched normal kidney. Immunohistochemistry demonstrates KIT protein expression on the membrane of ChRCC tumor cells. Of the 14 metastatic ChRCC specimens stained for KIT at our institution, 85% (12) were positive. In the TCGA, mRNA levels of SCF (KITLG), the KIT ligand, in ChRCC are the second highest compared to other tumors, and in published single-cell RNA sequencing data, KIT and SCF are co-expressed in ChRCC tumor cells. We found that KIT (CD117) mRNA expression is significantly higher in ChRCC-derived cells compared to ccRCC-derived cells and HK cells (derived from normal human kidney). Western blot analysis confirmed KIT expression in five ChRCC cell lines. Despite the high KIT expression, knockdown of KIT or treatment with Imatinib, a tyrosine kinase inhibitor that targets KIT, did not decrease the proliferation of ChRCC-derived cells. This indicates that KIT is not driving the proliferation of ChRCC cells. LOP628 is a KIT ADC consisting of the anti-KIT antibody LMJ729 conjugated to the microtubule destabilizing maytansinoid DM1. The two ChRCC cell lines with the highest expression of KIT (RCJ T1 and RCJT2) and ccRCC-derived 786-0 cells (with low KIT expression, as a control) were treated with 20nM of LOP628 for 24 hours. LOP628 decreased the viability of the ChRCC-derived cells by ∼60% with no effect on the ccRCC cells. Conclusions: KIT and its ligand SCF are highly expressed by ChRCC cells and LOP628, a KIT ADC, decreases ChRCC cell proliferation. Citation Format: Michel Alchoueiry, Hadi Mansour, Damir Khabibullin, Tiegang Han, Saireudee Chaturantabut, Jessica F. Williams, Michelle S. Hirsch, Carmen Priolo, William R. Sellers, Elizabeth P. Henske. Targeting KIT in chromophobe renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2119.