FGFR-Mediated Reactivation of MAPK Signaling Attenuates Antitumor Effects of Imatinib in Gastrointestinal Stromal Tumors

被引:91
作者
Li, Fang [1 ]
Huynh, Hung [2 ]
Li, Xiaoyan [1 ]
Ruddy, David A. [1 ]
Wang, Youzhen [1 ]
Ong, Richard [2 ]
Chow, Pierce [2 ]
Qiu, Shumei [1 ]
Tam, Angela [1 ]
Rakiec, Daniel P. [1 ]
Schlegel, Robert [1 ]
Monahan, John E. [1 ]
Huang, Alan [1 ]
机构
[1] Novartis Inst BioMed Res, Oncol Translat Res, Cambridge, MA 02139 USA
[2] Natl Canc Ctr, Lab Mol Endocrinol, Div Mol & Cellular Res, Singapore, Singapore
关键词
RECEPTOR TYROSINE KINASE; FEEDBACK INHIBITION; ACQUIRED-RESISTANCE; DOSE IMATINIB; CELL-LINE; PHASE-II; C-KIT; GROWTH; MUTATIONS; MESYLATE;
D O I
10.1158/2159-8290.CD-14-0763
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GIST). Although treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines and improved efficacy in patient-derived GIST xenografts. In addition, inhibition of MAPK signaling by imatinib was not sustained in GIST cells. An ERK rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregulation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells. SIGNIFICANCE: We here show that FGFR-mediated reactivation of the MAPK pathway attenuates the antiproliferation effects of imatinib in GISTs. The imatinib-induced ERK rebound can be repressed by the FGFR inhibitor BGJ398, and combined KIT and FGFR inhibition leads to increased efficacy in vitro and in patient-derived xenografts. (C)2015 AACR.
引用
收藏
页码:438 / 451
页数:14
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