title: Rational combination of MEK inhibitor and the STAT3 pathway modulator for the therapy in K-Ras mutated pancreatic and colon cancer cells.
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.
authors.affiliation: School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, People's Republic of China.|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.|Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, University Town, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Chengguang
authors.initials: C
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, University Town, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.affiliation: School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Shulin
authors.initials: S
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D050796:STAT3 Transcription Factor; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: K-Ras; MEK inhibitor; STAT3; colon cancer; pancreatic cancer