The antibody-drug conjugate sacituzumab govitecan (IMMU-132) represents a potential novel therapeutic strategy in cholangiocarcinoma.

Cholangiocarcinoma is a rare and aggressive cancer type with limited therapeutic options. Several novel antibody-drug conjugates (ADCs) have demonstrated promising anti-tumor activity in solid tumors. This study aimed to investigate the expression and the potential prognostic role of the protein targets of the recently-developed ADCs, in cholangiocarcinoma. Moreover, the study aimed to establish patient-derived tumor organoids (PDOs) and to employ them for in vitro ADC testing. We evaluated the expression of TROP2, NECTIN4, folate receptor 1, HER2, and HER3 via immunohistochemistry (IHC) in a cholangiocarcinoma tissue microarray (TMA) (n=113) and analyzed the expression level with respect to clinico-pathological parameters. Furthermore, we generated cholangiocarcinoma PDO culture lines and used them to test the anti-tumor activity of ADCs in vitro. IHC analyses revealed that TROP2 was the most frequently expressed (91% of cases), followed by folate receptor 1 (51%), NECTIN4 (49%), HER3 (20%), and HER2 (7%). TROP2 showed moderate to high expression (H-score ≥100) in 74% of cases. No significant correlations with overall or disease-free survival, tumor grade, or tumor stage were observed. Six cholangiocarcinoma PDO lines were successfully established (55% success rate). All PDO lines expressed TROP2 concordantly with their parental tumors and showed growth-inhibition (IC50= 0.1 to 0.4 µg/mL) in response to sacituzumab govitecan (TROP2-targeting ADC). This study reveals that TROP2 is widely expressed in cholangiocarcinoma. Moreover, it provides preclinical evidence for the potential of use of sacituzumab govitecan as a novel therapeutic strategy in treating cholangiocarcinoma patients.