Inhibition Of Erk1/2 Can Sensitize Human Malignant Mesothelioma Cells And Tumors To Doxorubicin

Malignant mesothelioma (MM) has a poor prognosis because of its resistance towards different drugs. Extracellular signal regulated kinase (ERK) family is known to have important roles in tumorigenesis and drug resistance. Here we show that Doxorubicin (Dox) treatment activates ERK1/2 in different MM lines. Activated ERK1/2 play a significant role in cell survival as inhibition of ERK1/2 by U0126 in the presence of Dox results in significantly enhanced cell killing. We show here using small molecule inhibitor and RNA silencing approaches that ERK1/2 inhibition sensitizes human MM cells to Dox treatment. ERK1/2 inhibition by U0126 significantly inhibited certain important drug resistance and proapoptotic genes in human MM cells as measured by PCR Array using human drug resistance and metabolism template. MM cell lines stably transfected with shERK1 or shERK2 exhibited significant increases in the accumulation of Dox and decreases in the cell viability when treated with Dox as compared to shCon line. Microarray analysis performed on stable shERK1 and shERK2 lines showed more than 2 fold inhibitions in selected ATP binding cassette genes, which may be responsible in part for increased Dox accumulation and sensitivity. Finally, subcutaneous injection of stable human MM lines inhibited for ERK1 or ERK2 into SCID mice showed that inhibition of ERK1/2 sensitizes in vivo tumors to Dox. These studies demonstrate a key role of ERK1/2 in MM tumor drug resistance. This work is supported by National Cancer Institute grant P01CA114047 and VCC/LCCRO grant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 347.