Abstract B65: Antitumor activity of imatinib in GIST is attenuated by FGFR signaling.

Activating mutations in either KIT or PDGFR are present in approximately 90% of gastrointestinal stromal tumors (GISTs). Treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients. However, the beneficial effect is not durable with more than 50% of patients progressing after 2 years of imatinib first line therapy. Gene expression data has revealed that FGF2 and FGFR1 are highly expressed in all primary GIST samples examined and at significantly higher levels than the other forty tumor types tested, suggesting that FGFR signaling may limit the antitumor response of imatinib. The effect of inhibiting FGFR signaling in GIST cell lines was tested by combining imatinib with BGJ398, a potent and selective small-molecule inhibitor of FGFR1, FGFR2, and FGFR3. This combination showed increased growth inhibition in imatinib-sensitive GIST cell lines. This effect was observed in the presence or absence of added FGF2. The degree of synergy generated by imatinib and BGJ398 combination correlated with the level of added FGF2. In addition, inhibition of mitogen-activated protein kinase (MAPK) was transient in GIST cells treated with imatinib. The re-activation of extracellular signal-regulated kinase (ERK) in GIST cells was accompanied by increased FGFR signaling, and can be suppressed by BGJ398 treatment. These results suggest that imatinib treatment induces feedback activation of FGFR signaling that can attenuate the antitumor effects of imatinib. This provides a rationale for combining imatinib and FGFR inhibitors, such as BGJ398, in the first line therapy of GIST. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B65. Citation Format: Fang Li, Joseph Growney, Linda Battalagine, Shumei Qiu, Paul Manley, Robert Schlegel, John Monahan. Antitumor activity of imatinib in GIST is attenuated by FGFR signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B65.