Background
Heat shock protein 90 (HSP90) is a protein chaperon and plays an essential role in maintaining stability and activity of its clients, including many proteins involved in the pathogenesis of cancer. A number of HSP90 inhibitors have been developed and entered clinical trials in the treatment of various types of cancers. However, primary and acquired resistance remains a barrier for curative treatment with these inhibitors.
Aims
To elucidate resistance mechanisms of human colon cancer cells to HSP90 inhibitors, thus providing information for development of approaches to overcome the resistance
Results
Treatment with the HSP90 inhibitor AUY922 markedly reduced cell viability in approximately half of the colon cancer cell lines tested, which was associated with activation of the mitochondrial apoptotic pathway and the caspase cascade, and was inhibited by the general caspase inhibitor z-VAD-fmk, indicative of induction of apoptosis. Strikingly, while AUY922 caused progressive reduction in activation of Akt and ERK in sensitive colon cancer cells, inhibition of Akt and ERK activation in resistant cells after exposure to the inhibitor appeared transient and was followed by marked rebound activation. Co-treatment with the MEK inhibitor U0126 or the PI3K/Akt inhibitor LY294002 rendered resistant cells sensitive to AUY922-induced apoptosis, whereas ectopic expression of an active form of MEK or Akt protected sensitive cells from apoptosis induced by the inhibitor.
Conclusions
These results identify reactivation of Akt and ERK as an important resistance mechanism of colon cancer cells to HSP90 inhibitors, and suggest that co-targeting PI3K/Akt and/or MEK/ERK in combination of HSP90 inhibitors may be a useful strategy to improve the therapeutic efficacy in the treatment of colon cancer.
Translational research aspect
This project is currently at T1 stage. Given that specific inhibitors against MEK/ERK, PI3K/Akt, or HSP90 are either in clinic use or in clinical studies, it is expected that the results will be taken into T2-T4 studies in near future.