The cytotoxic action of BCI is not dependent on its stated DUSP1 or DUSP6 targets in neuroblastoma cells

Neuroblastoma (NB) is a complex childhood cancer of the nervous system, representing a significant portion of pediatric malignancies. Due to limited targetable molecular abnormalities, treatment options are often nonspecific. This study explored the therapeutic potential of BCI, an inhibitor of DUSP1 and DUSP6, in NB cell cultures.

BCI showed cytotoxic effects across various NB cell lines. It induced a transient activation of AKT and stress-related MAP kinases, but did not affect ERK phosphorylation. A phosphoproteomic screen revealed increased JNK signaling and decreased mTOR and R6K signaling.

To evaluate BCI’s specificity, CRISPR-Cas9 was used to create DUSP1 and DUSP6 gene mutations. Surprisingly, BCI remained fully cytotoxic in NB cells with complete DUSP6 loss and partial DUSP1 depletion. This suggests BCI’s cytotoxicity in NB cells involves a complex mechanism independent of these phosphatases.

These findings highlight the risk of relying on inhibitors like BCI as supposedly specific DUSP1/6 inhibitors without fully understanding their targets in cancer cells. MRTX-1257