The antirheumatoid agent
aurothiomalate (ATM) is a potent inhibitor of oncogenic
PKC iota. ATM inhibits non-small
lung cancer (NSCLC) growth by binding
PKC iota and blocking activation of a PKC iota-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 approximately 300 nmol/L to >100 micromol/L. ATM sensitivity correlates positively with expression of
PKC iota and Par6, but not with the
PKC iota binding protein p62, or the proposed targets of ATM in
rheumatoid arthritis (RA),
thioredoxin reductase 1 or 2.
PKC iota expression profiling revealed that a significant subset of primary NSCLC
tumors express
PKC iota 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
PKC iota and Par6. Our results indicate that
PKC iota expression profiling will be useful in identifying
lung cancer patients most likely to respond to ATM
therapy in an ongoing clinical trial.