AZD6244 inhibits cisplatin-induced ERK1/2 activation and potentiates cisplatin-associated cytotoxicity in K-ras G12D preclinical models

作者：Kim Eun Young; Kim Arum; Kim Se Kyu; Chang Yoon Soo^*

来源：Cancer Letters, 2015, 358(1): 85-91.

DOI：10.1016/j.canlet.2014.12.041

• Bcl2-like 11 (BIM)
• MEK1/2 inhibitor
• Cisplatin
• KRAS
• NSCLC

Although cisplatin has been widely used as a component of standard treatments for advanced nonsmall cell lung cancers (NSCLC) with KRAS-activating mutations, clinical outcomes remain suboptimal. Among the resistance mechanisms to cisplatin, activation of the MAPK cascade, which plays an important role in cancer cell stress and death, offers a promising therapeutic target. Using KRAS-mutant NSCLC cells and a mouse model, we evaluated the efficacy of adding the MEK1/2 inhibitor AZD6244 as an addition for cisplatin-based chemotherapy. Cisplatin increased phosphorylation of MEK1/2 and ERK1/2 and reduced Bcl-2 like 11 (BIM) expression in NSCLC cells and the mouse model. BIM silencing in NSCLC cells using shRNA led to a blunted cytotoxic response to cisplatin, while prevention of BIM loss with the MEK1/2 inhibitor synergized cisplatin-mediated cell death. The combination of cisplatin and AZD6244 yielded a superior response to cisplatin alone in K-ras mice. In conclusion, an MEK1/2 inhibitor potentiated the anti-tumor effects of cisplatin in KRAS-dependent lung cancer cells and an animal model through inhibition of BIM degradation. These findings warrant further studies of clinical applications of MEK1/2 inhibitors in cisplatin-based chemotherapy for lung cancer.

• 出版日期2015-3-1