American Journal of Respiratory Cell and Molecular Biology. 2014 June 18. [Epub ahead of print] [Link]
Beuschel SL, Hillegass JM, MacPherson MB, Macura SL, Miller JM, Mossman BT, Perkins TN, Sayan M, Shukla A, Thompson JK.
Malignant mesothelioma (MM), lung cancers and asbestosis are hyper-proliferative diseases associated with exposures to asbestos. All have a poor prognosis, thus the need to develop novel and effective therapies is urgent. Vandetanib (Van) (ZD6474, ZACTIMAâ„¢) is a tyrosine kinase inhibitor (TKI) that has shown equivocal results in clinical trials for advanced non-small cell lung cancer. However, TKIs alone have shown no significant clinical activity in phase II trials of patients with unresectable MM. Using epithelioid (HMESO) and sarcomatoid (H2373) human MM lines, the efficacy of tumor cell killing and signaling pathways modulated by Van with and without Doxorubicin (Dox) were examined. Van alone reduced total cell numbers in the HMESO MM. Moreover, it synergistically increased the toxicity of Dox in both HMESO and H2373 cells. Van also caused the inhibition of Dox-induced phosphorylation of the epidermal growth factor receptor (EGFR), extracellular signal-regulated kinases (ERK1, ERK2), and protein kinase A (AKT). Most importantly, we identified two novel cell survival/resistance pathways, ERK5, and cAMP response element binding protein (CREB) that were inhibited by Van and Dox.. After silencing of either ERK5 or CREB, significant decreases in cell numbers in the Dox-resistant sarcomatoid H2373 line were observed. Results suggest that a plethora of cell signaling pathways associated with cell survival are induced by Dox, but inhibited by addition of Van in MMs. Data advocate the combined efficacy of Van and Dox as a novel approach in the treatment of MM that is further enhanced by blocking ERK5 or CREB signaling cascades.