Among the players of the adaptive response of
cancer cells able to promote a resistant and aggressive phenotype,
carbonic anhydrase IX (CAIX) recently has emerged as one of the most relevant drug targets. Indeed, CAIX targeting has received a lot of interest, and selective inhibitors are currently under clinical trials.
Hypoxia has been identified as the master inductor of CAIX, but, to date, very few is known about the influence that another important characteristic of tumor microenvironment, i.e., extracellular
acidosis, exerts on CAIX expression and activity. In the last decades, acidic microenvironment has been associated with aggressive
tumor phenotype endowed with epithelial-to-mesenchymal transition (EMT) profile, high invasive and migratory ability, apoptosis, and drug resistance. We demonstrated that
melanoma, breast, and
colorectal cancer cells transiently and chronically exposed to acidified medium (pH 6.7 ± 0.1) showed a significantly increased CAIX expression compared to those grown in standard conditions (pH 7.4 ± 0.1). Moreover, we observed that the CAIX inhibitor
FC16-670A (also named SLC-0111, which just successfully ended phase I clinical trials) not only prevents such increased expression under
acidosis but also promotes apoptotic and necrotic programs only in acidified
cancer cells. Thus, CAIX could represent a selective target of acidic
cancer cells and
FC16-670A inhibitor as a useful tool to affect this aggressive subpopulation characterized by conventional
therapy escape.
KEY MESSAGES:
Cancer cells overexpress CAIX under transient and chronic extracellular
acidosis.
Acidosis-induced CAIX overexpression is NF-κB mediated and HIF-1α independent.
FC16-670A prevents CAIX overexpression and induces acidified
cancer cell death.