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,Chenglong Li,Xiaojuan Wu,Jiayuh Lin,Guang Liang,Shulin Yang

doi:10.18632/oncotarget.3991

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.

Highlights

Ras proteins play a direct causal role in human cancers
Increased Signal Transducer and Activator of Transcription 3 (STAT3) and JAK2 phosphorylation induced by MEK inhibitors in K-Ras mutant pancreatic cancer cells
To investigate whether MEK inhibitors activate JAK2/STAT3 signal pathways, we examined the effects of MEK inhibitors in K-Ras mutant cancer cell lines

Summary

Introduction

Ras proteins play a direct causal role in human cancers. Oncogenic mutant Ras proteins are highly prevalent in multiple human tumors (~30% of all human tumors), with mutations of K-Ras being the major clinical problem [1]. K-Ras signals via downstream effectors such as MAPK, PI3K/AKT and STAT3 signaling cascade [19,20,21] It has been shown MAPK signaling plays a more important role in tumor maintenance than PI3K signaling in K-Ras mutant pancreatic and lung tumors [22, 23]. Drug development efforts have mostly focused on components of the classical Ras-activated MAPK pathway As part of this pathway, MEK1/2, a dual-specific kinase required for activation of ERK1/2, plays crucial roles in tumorigenesis, cell proliferation and inhibition of apoptosis, MEK1/2 inhibition is an attractive therapeutic strategy in a number of cancers. Resistance to MEK inhibitors has been reported in pancreatic cancer and colon carcinoma with Ras mutations. Elucidating the mechanism of cancer cell resistance to MEK inhibitors is critical for the development of more effective therapies

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