The CAIX inhibitor SLC-0111 exerts anti-cancer activity on gastric cancer cell lines and resensitizes resistant cells to 5-Fluorouracil, taxane-derived, and platinum-based drugs

• Published in: Cancer letters 2023-09, Vol.571, p.216338-216338, Article 216338
• Main Authors: Andreucci, Elena, Biagioni, Alessio, Peri, Sara, Versienti, Giampaolo, Cianchi, Fabio, Staderini, Fabio, Antonuzzo, Lorenzo, Supuran, Claudiu T., Olivo, Erika, Pasqualini, Elisa, Messerini, Luca, Massi, Daniela, Lulli, Matteo, Ruzzolini, Jessica, Peppicelli, Silvia, Bianchini, Francesca, Schiavone, Nicola, Calorini, Lido, Magnelli, Lucia, Papucci, Laura
• Format: Article
• Language: English
• Subjects: Carbonic anhydrase IX; Chemoresistance; Gastric cancer; Perioperative chemotherapy
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2023.216338

Gastric cancer (GC) is the fifth most frequent malignancy and the fourth leading cause of worldwide cancer-related death. Despite the usage of multimodal perioperative chemotherapy (pCT), GC progressively gains chemoresistance, thereby, the identification of suitable targets to overcome drug resistance is fundamental. Amongst the potential biomarkers, carbonic anhydrase IX (CAIX) - associated with a poor prognosis of several solid cancers - has gained the most attention. In a cohort of GC patients who received perioperative FLOT (i.e., Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) or FOLFOX (i.e., Leucovorin, 5-Fluouracil, and Oxaliplatin), non-responder patients showed an increased expression of tumor CAIX compared to responder group. Moreover, GC cell lines induced to be resistant to 5-Fluouracil, Paclitaxel, Cisplatin, or the combination of 5-Fluorouracil, Oxaliplatin, and Docetaxel, overexpressed CAIX compared to the control. Accordingly, CAIX-high-expressing GC cells showed increased therapy resistance compared to low-expressing cells. Notably, SLC0111 significantly improved the therapy response of both wild-type and resistant GC cells. Overall, these data suggest a correlation between CAIX and GC drug resistance highlighting the potential of SLC-0111 in re-sensitizing GC cells to pCT. •CAIX increases in non-responder GC patients to pCT compared to the responder group.•GC resistance to pCT is accompanied by CAIX overexpression in vitro.•The CAIX inhibitor SLC-0111 re-sensitizes resistant GC cells to pCT.•The CAIX inhibitor SLC-0111 improves GC cell response to pCT.