Journal
ONCOTARGET
Volume 6, Issue 16, Pages 14472-14487Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3991
Keywords
STAT3; K-Ras; MEK inhibitor; pancreatic cancer; colon cancer
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Funding
- AACR-Pancreatic cancer Network research grant
- National Natural Science Funding of China [81202462, 81302642]
- OSUCCC DDI
- NIH/NCI/R21 [CA173473-01]
- Technology Development Fund from Research Institute at Nationwide Children's Hospital
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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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