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

Chromophobe renal cell carcinoma (ChRCC) is the second most common variant histology (non-clear cell) RCC. Despite progress in treating other kidney cancer subtypes, ChRCC lacks molecularly tailored strategies. Response rates to tyrosine kinase, mTOR inhibitors, and immunotherapy are generally limited. The identification of KIT as a promising therapeutic target in this study represents an important step forward.

KIT (also known as CD117 and c-KIT) is a receptor tyrosine kinase that plays a key role in cell survival, proliferation, and differentiation. While KIT has long been recognized as a diagnostic marker in ChRCC, its potential as a therapeutic anchor has not been fully explored. KIT has the highest mRNA expression across all tumors in The Cancer Genome Atlas (TCGA). KIT is not mutated in ChRCC, in contrast to some other tumor types, such as GI Stromal Tumors (GIST), which have a high rate of activating KIT mutations. Crucially, we found that KIT is localized to the cell surface in ChRCC primary tumors and metastases. This makes it amenable to targeting with antibody-drug conjugates (ADCs), offering a new therapeutic angle not previously considered in this context.

Using a KIT-targeting ADC, we demonstrated selective efficacy in ChRCC-derived models. These findings support a paradigm in which wild-type receptor expression can be leveraged for selective delivery of cytotoxic payloads.

Of particular clinical importance, a Phase I trial (NCT06805825) evaluating a KIT-targeted ADC (NN3201, a human monoclonal KIT antibody conjugated to the microtubule disrupting cytotoxic agent monomethyl auristatin E (MMAE)) is now open at seven sites in the US and includes patients with ChRCC, offering a much-needed opportunity to translate these recently published findings into therapeutic benefit.

This work repositions KIT as a functional therapeutic target in ChRCC and highlights the potential of ADCs in addressing the unmet needs of rare tumor types.

Written by: Michel Alchoueiry,¹ Hadi Mansour,¹ Damir Khabibullin,¹ Tiegang Han,¹ Saireudee Chaturantabut,² Wafaa Bzeih,¹ Yan Tang,¹ Jessica F. Williams,³ Michelle S. Hirsch,³ Carmen Priolo,¹ William R. Sellers,² Elizabeth P. Henske¹

Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Broad Institute of MIT and Harvard; Cambridge, MA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

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