1679P - Mutant KIT Translocates into the Nucleus and Induces NFKBIB Expression that Leads to KIT Expression in Imatinib-Resistant Gastrointestinal Stromal...

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Anti-Cancer Agents & Biologic Therapy
Translational Research
Presenter Yuan-Shuo Hsueh
Citation Annals of Oncology (2017) 28 (suppl_5): v573-v594. 10.1093/annonc/mdx390
Authors Y. Hsueh1, H.H. Chang2, Y. Shan3, H..S. Sun4, J.A. Fletcher5, C. Li6, L. Chen1
  • 1National Institute Of Cancer Research, National Health Research Institutes, 704 - Tainan/TW
  • 2Institute Of Clinical Pharmacy And Pharmaceutical Sciences, College Of Medicine, National Cheng Kung University, Tainan, Taiwan, 701 - Tainan/TW
  • 3Department Of Surgery, National Cheng Kung University Hospital, 704 - Tainan/TW
  • 4Institute Of Molecular Medicine, College Of Medicine, National Cheng Kung University, 701 - Tainan/TW
  • 5Department Of Pathology, Brigham and Women’s Hospital and Harvard Medical School, 02115 - Boston/US
  • 6Department Of Pathology, Chi-Mei Foundation Medical Center, 710 - Tainan/TW



Gastrointestinal stromal tumor (GIST) is a dominantly mutant KIT-driven tumor. Prolonged tyrosine kinase inhibitor (TKI) treatment may result in a resistant phenotype through acquired secondary KIT mutation. Increasing evidences show that membrane-bound receptors, as EGFR, can translocate into the nucleus, mediate genes expression, and lead to tumor survival and drug resistance. However, it’s barely known the nuclear role of KIT in GIST.


In this study, two imatinib (IM)-resistant GIST cell lines, GIST48 and GIST430, were used as a model.


In this study, we first showed that KIT is distributed both in the cytoplasm and the nucleus in IM-resistant GIST cells. Using ChIP-seq and ChIP assay, we identified that nuclear KIT bound to the NFKBIB promoter region and regulated its expression. The expression levels of NFKBIB and phosopho-KIT were significantly correlated with NCCN-risk category in surgically resected GISTs stained by immunohistochemistry. The cell viabilities were inhibited as accompanying with KIT reduction in GIST cells while NFKBIB was silenced or RELA was overexpressed. Moreover, RELA was activated, translocated into the nucleus, and bound to KIT promoter region in NFKBIB-silenced or RELA-overexpressed GIST cells. Valproic acid, acted as a NFKB inducer, could induce RELA nucleus translocation and binding to KIT promoter region that led to the reduction of protein and RNA expression level of KIT and the cell viabilities of GIST cells. Furthermore, the combination of IM with low-dose valproic acid showed synergistically inhibitory effect on cell viabilities of GIST cells and comparable effects on reducing phospho-KIT level and inhibiting tumor growth as high-dose valproic acid did in GIST430 xenograft model.


Taken together, we first demonstrated that phosphorylated KIT could translocate into the nucleus and drive itself expression in IM-resistant GIST cells through mediating NFKBIB expression. In addition, our findings identified a novel and druggable KIT-NFKBIB-NFKB regulatory axis that provides a new insight on tumorigenesis and therapeutic option for IM-resistant, mutant KIT-expressing GISTs.

Clinical trial identification

Legal entity responsible for the study

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan


National Health Research Institutes, Taiwan and the Ministry of Science and Technology, Taiwan.


Y-S. Hsueh: Research funds were provided by the Ministry of Science and Technology, Taiwan. L-T. Chen: Research funds were provided by the National Health Research Institutes, Taiwan. All other authors have declared no conflicts of interest.