An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo

Carbonic anhydrase XII (CAXII) is a membrane‐tethered ectoenzyme involved in intracellular pH regulation and overexpressed across various types of human cancer. Because CAXII inhibition shows antitumor activity in vitro, it is thought that the enzyme is mandatory for maximum tumor growth, above all under hypoxic conditions. Recently, it has been shown that CAXII is co‐expressed along with the P‐glycoprotein (P‐GP) on many tumor cells and that both proteins physically interact. Of interest, blocking CAXII activity also decreases P‐GP activity in cancer cells both in vitro and in vivo. Previously, we have reported on the development of a monoclonal antibody, termed 6A10, which specifically and efficiently blocks human CAXII activity. Here, we demonstrate that 6A10 also indirectly reduces P‐GP activity in CAXII/P‐GP double‐positive chemoresistant cancer cells, resulting in enhanced chemosensitivity as revealed by enhanced accumulation of anthracyclines and increased cell death in vitro. Even more important, we show that mice carrying human triple‐negative breast cancer xenografts co‐treated with doxorubicin (DOX) and 6A10 show a significantly reduced number of metastases. Collectively, our data provide evidence that the inhibition of CAXII with 6A10 is an attractive way to reduce chemoresistance of cancer cells and to interfere with the metastatic process in a clinical setting. What's new? Through the reversible hydratation of carbon dioxide, carbonic anhydrases (CAs) produce bicarbonate, a critical mediator of pH homeostasis. In human cancers, however, certain forms of CA are overexpressed and may provide a survival advantage for hypoxic tumor cells in acidic tumor environments. Here, using a monoclonal antibody, 6A10, the authors show that inhibition of cancer‐associated CAXII enhances chemosensitivity in resistant cancer cells. In an orthotopic breast cancer mouse model, co‐treatment with 6A10 and doxorubicin had no inhibitory effect on primary tumor growth. In tumor‐bearing animals, however, co‐treatment with the drugs significantly reduced the number of lung metastases.