FGFR-Mediated Reactivation of MAPK Signaling Attenuates Antitumor Effects of Imatinib in Gastrointestinal Stromal Tumors
Menée sur des lignées cellulaires et à l'aide de xénogreffes dérivées de patients atteints d'une tumeur stromale gastrointestinale, cette étude met en évidence des mécanismes suggérant l'intérêt de combiner un inhibiteur de FGFR à l'imatinib pour surmonter une résistance thérapeutique
Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GISTs). 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 mitogen-activated protein kinase (MAPK) signaling by imatinib was not sustained in GIST cells. An extracellular signal-regulated kinase (ERK) rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregultation 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 MAPK pathway attenuates the anti-proliferation 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.