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Published on: January 22, 2013
Targeting KIT With Antibody-Drug Conjugates in Chromophobe Renal Cell Carcinoma
Michel Alchoueiry1, Hadi Mansour1, Damir Khabibullin1
1Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Introduction:
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.
Results:
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.
Conclusion:
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.
Insights
KIT (CD117) is highly expressed in chromophobe renal cell carcinoma (ChRCC). A KIT antibody-drug conjugate (ADC) effectively reduced ChRCC cell viability, indicating KIT is a promising therapeutic target for advanced ChRCC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Chromophobe renal cell carcinoma (ChRCC) is the third most common kidney cancer subtype.
- Metastatic ChRCC lacks effective therapies, with a median survival of 27 months.
- KIT (CD117) is a cell surface receptor tyrosine kinase implicated in various cancers.
Purpose of the Study:
- To investigate KIT expression in ChRCC.
- To evaluate the efficacy of KIT-targeted antibody-drug conjugates (ADCs) in ChRCC models.
Main Methods:
- Analysis of KIT mRNA expression in The Cancer Genome Atlas and patient specimens.
- Western blot and single-cell RNA sequencing to confirm KIT expression in ChRCC cells.
- Assessment of cell viability after treatment with a KIT ADC (LOP628) in ChRCC and clear cell renal cell carcinoma (ccRCC) cell lines.
Main Results:
- KIT mRNA and protein expression are significantly elevated in ChRCC compared to normal kidney tissue and ccRCC.
- 87% of metastatic ChRCC specimens showed positive KIT staining.
- A KIT ADC (LOP628) demonstrated significant ChRCC cell killing (∼60% viability reduction) without affecting ccRCC cells.
Conclusions:
- KIT is a highly relevant and viable therapeutic target for antibody-drug conjugate development in ChRCC.
- These findings support further clinical investigation of KIT-targeted therapies for metastatic ChRCC.
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