Atypical protein kinase CL expression and aurothiomalate sensitivity in human lung cancer cells

The antirheumatoid agent aurothiomalate (ATM) is a potent inhibitor of oncogenic PKCL. ATM inhibits non-small lung cancer (NSCLC) growth by binding PKCL and blocking activation of a PKCL-Par6-Rac1-Pak-Mek 1,2-Erk 1,2 signaling pathway. Here, we assessed the growth inhibitory activity of ATM in a panel of human cell lines representing major lung cancer subtypes. ATM inhibited anchorage-independent growth in all lines tested with IC(50)s ranging from similar to 300 nmol/L to > 100 mu mol/L. ATM sensitivity correlates positively with expression of PKCL. and Par6, but not with the PKCL binding protein p62, or the proposed targets of ATM in rheumatoid arthritis (RA), thioredoxin reductase 1 or 2. PKCL expression profiling revealed that a significant subset of primary NSCLC tumors express PKCL at or above the level associated with ATM sensitivity. ATM sensitivity is not associated with general sensitivity to the cytotoxic agents cis-platin, placitaxel, and gemcitabine. ATM inhibits tumorigenicity of both sensitive and insensitive lung cell tumors in vivo at plasma drug concentrations achieved in RA patients undergoing ATM therapy. ATM inhibits Mek/Erk signaling and decreases proliferative index without effecting tumor apoptosis or vascularization in vivo. We conclude that ATM exhibits potent antitumor activity against major lung cancer subtypes, particularly tumor cells that express high levels of the ATM target PKCL and Par6. Our results indicate that PKCL expression profiling will be useful in identifying lung cancer patients most likely to respond to ATM therapy in an ongoing clinical trial.