Oncotarget

Research Papers:

Rational combination of MEK inhibitor and the STAT3 pathway modulator for the therapy in K-Ras mutated pancreatic and colon cancer cells

Chengguang Zhao, Hui Xiao, Xiaojuan Wu, Chenglong Li, Guang Liang, Shulin Yang and Jiayuh Lin _

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Oncotarget. 2015; 6:14472-14487. https://doi.org/10.18632/oncotarget.3991

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Abstract

Chengguang Zhao1,2,3, Hui Xiao2, Xiaojuan Wu2, Chenglong Li4, Guang Liang3, Shulin Yang1 and Jiayuh Lin2

1 School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, People’s Republic of China

2 Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA

3 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, University Town, Wenzhou, Zhejiang, People’s Republic of China

4 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA

Correspondence to:

Jiayuh Lin, email:

Shulin Yang, email:

Keywords: STAT3; K-Ras; MEK inhibitor; pancreatic cancer; colon cancer

Received: February 23, 2015 Accepted: April 08, 2015 Published: May 04, 2015

Abstract

K-Ras mutations are frequently detected in pancreatic and colon cancers, which are associated with the resistance to MEK inhibitors targeting the Ras pathway. Identifying the underlying mechanisms for the acquired resistance is essential for the future clinical development of MEK inhibitors. Here, we identified that Signal Transducer and Activator of Transcription 3 (STAT3) was significantly activated following the MEK inhibition using AZD6244, PD98059 and Trametinib in K-Ras mutant pancreatic and colon cancer cells. The STAT3 activation may be important for the MEK inhibitor resistance in these K-Ras mutant cancer cells. We have shown that dual inhibition of STAT3 and MEK using the STAT3 inhibitor LY5 and MEK inhibitor Trametinib exerts significant anti-tumor cell efficacy in K-Ras mutant pancreatic and colon cancer cells in vitro. In addition, Trametinib showed increased suppression on tumor growth in vivo in STAT3 knockdown pancreatic cancer cells compared with tumor growth of control cells without STAT3 knockdown. Taken together, our results suggest the induced STAT3 activation as a possible mechanism for the resistance to MEK inhibitor and demonstrate the potentials of a combination therapy using MEK and STAT3 inhibitors in pancreatic and colon cancers harboring K-Ras mutant proteins.


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