Low dose HSP90 inhibition with AUY922 blunts rapid evolution of metastatic and drug resistant phenotypes induced by TGF-β and paclitaxel in A549 cells

Abstract

Objectives: Despite advances in cancer treatment, drug resistance and metastasis continue to contribute to treatment failure. Since drug resistance and metastasis in cancer are features that often occur toward the late stages in the disease after withstanding numerous selective pressures, they may rely on a shared adaptive mechanism in order to persist. The heat shock response is one of the most well conserved adaptive responses to cellular stress found in nature. A major player in the heat shock response is HSP90, with some studies suggesting that it can facilitate the molecular evolution of drug resistance and metastasis in cancer. Non-small cell lung cancers (NSCLCs) are strongly associated with drug resistance and metastasis either at the time of diagnosis or early in the treatment process.

Materials and methods: We explored the role of HSP90 in the evolution of metastatic and drug resistant features in NSCLC by treating A549 cells with AUY922, a clinically relevant HSP90 inhibitor, and inducing metastatic and drug resistant phenotypes via treatment with TGF-β and paclitaxel, respectively. We measured phenotypic plasticity in E-Cadherin, a marker for epithelial to mesenchymal transition and two ABC transporters associated with drug resistant lung cancers.

Results: We found that metastatic and efflux dependent drug resistant features negatively correlated with AUY922 treatment. We followed our results with functional assays relevant to metastasis and ABC transporters to confirm our results. Specifically we found the expression of E-cadherin was significantly increased in A549 cultures pretreated with AUY922 prior to exposure to paclitaxel, while expression of the drug transporters ABCB1 and ABCC1 was significantly reduced under similar conditions.

Conclusion: Together our data indicates that HSP90 inhibition with AUY922 can limit the acquisition of metastatic and drug resistant phenotypes in A549 cells at low, clinically appropriate doses.

Keywords: Drug resistance; HSP90 inhibitors; Lung cancer; Metastasis; Molecular evolution; Phenotypic plasticity.