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

Fang Li,Youzhen Wang,Angela Tam,Hung Huynh,Robert Schlegel,Richard Ong,Shumei Qiu,Pierce Chow,David A Ruddy,John E Monahan,Xiaoyan Li,Alan Huang,Daniel P Rakiec

doi:10.1158/2159-8290.cd-14-0763

Abstract

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. 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.

Highlights

Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma found in the gastrointestinal tract and are typically characterized by the expression of KIT [1, 2]
Primary resistance is defined as evidence of progression of disease within 6 months of imatinib treatment and is strongly associated with mutations in KIT exon 9 or PDGFRA exon 18 and with GISTs that are wild-type for both genes [9,10,11]
To identify the growth factors that potentially attenuate the antiproliferative effects of imatinib in GISTs, 317 cDNA constructs encoding 220 unique secreted or single-pass transmembrane proteins were transfected into HEK293T cells in 384-well plates in which each well was expected to contain a defined secreted protein

Summary

Introduction

Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma found in the gastrointestinal tract and are typically characterized by the expression of KIT [1, 2]. Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. Primary resistance is defined as evidence of progression of disease within 6 months of imatinib treatment and is strongly associated with mutations in KIT exon 9 or PDGFRA exon 18 and with GISTs that are wild-type for both genes [9,10,11]. Secondary resistance is observed in patients who respond to imatinib treatment initially and experience progression after 6 months of therapy. A recent study has shown that signaling cross-talk between KIT and FGFR3 promoted resistance to imatinib [16], suggesting that resistance to imatinib evolves by mechanisms other than acquired secondary mutations in KIT or PDGFRA. Viable tumor cells can be found in most patients who undergo tumor resections during imatinib therapy [17], suggesting that the residual GIST cells may exhibit adaptation to KIT or PDGFR inhibition through the activation of other pathways and the effect of imatinib on these cells is cytostatic rather than cytotoxic

Methods

Results

Conclusion