KIT over-expression by p55PIK-PI3K leads to Imatinib-resistance in patients with gastrointestinal stromal tumors.

// Senyan Lai 1, * , Guihua Wang 1, * , Xiaonian Cao 1 , Xuelai Luo 1 , Guoping Wang 2 , Xianmin Xia 3 , Junbo Hu 1 , Jing Wang 4 1 Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China 2 Department of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China 3 Department of Bioengineering, Hubei University of Technology, Wuhan, 430068, China 4 Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China * These authors have contributed equally to this work Corresponding to: Junbo Hu, e-mail: jbhu@tjh.tjmu.edu.cn Jing Wang, e-mail: wangj3599@163.com Keywords: p55PIK, Imatinib resistance, gastrointestinal stromal tumors Received: June 13, 2015      Accepted: October 09, 2015      Published: October 22, 2015 ABSTRACT Imatinib is the first-line drug for gastrointestinal stromal tumors (GISTs), as mutated KIT is closely associated with the occurrence of GIST. However, Imatinib resistance (IMA-resistance) occurs inevitably in most GIST patients. Although the over-expression of KIT in GIST is one of the major factors contributing to IMA-resistance, the underlying mechanism is still unclear. In this study, we demonstrate that p55PIK, an isoform of phosphoinositide 3-kinase (PI3K), increases KIT expression, leading to IMA-resistance in GISTs by activating NF-κB signaling pathway. Furthermore, down-regulation of p55PIK significantly decreases KIT expression and re-sensitizes IMA-resistance-GIST cells to Imatinib in vitro and in vivo . Interestingly, the expression of both p55PIK and KIT proteins is significantly increased in tumor samples from IMA-resistance-GIST patients, suggesting that p55PIK up-regulation may be important for IMA-resistance in the clinical setting. Altogether, our data provide evidence that p55PIK-PI3K signaling can contribute to IMA-resistance in GIST by increasing KIT expression. Moreover, p55PIK may be a novel potential drug target for treating tumors that develop IMA-resistance.