Inhibition of FGF2-Mediated Signaling in GIST—Promising Approach for Overcoming Resistance to Imatinib

Abstract

Inhibition of KIT-signaling is a major molecular target for gastrointestinal stromal tumor (GIST) therapy, and imatinib mesylate (IM) is known as the most effective first-line treatment option for patients with advanced, unresectable, and/or metastatic GISTs. We show here for the first time that the inhibition of KIT-signaling in GISTs induces profound changes in the cellular secretome, leading to the release of multiple chemokines, including FGF-2. IM increased migration, invasion, and colony formation of IM-resistant GISTs in an FGF2-dependent manner, whereas the use of blocking anti-FGF2 antibodies or BGJ398, a selective FGFR inhibitor, abolished these effects, thus suggesting that the activation of FGF2-mediated signaling could serve as a compensatory mechanism of KIT-signaling inhibited in GISTs. Conversely, FGF-2 rescued the growth of IM-naive GISTs treated by IM and protected them from IM-induced apoptosis, consistent with the possible involvement of FGF-2 in tumor response to IM-based therapy. Indeed, increased FGF-2 levels in serum and tumor specimens were found in IM-treated mice bearing IM-resistant GIST xenografts, whereas BGJ398 used in combination with IM effectively inhibited their growth. Similarly, increased FGF-2 expression in tumor specimens from IM-treated patients revealed the activation of FGF2-signaling in GISTs in vivo. Collectively, the continuation of IM-based therapy for IM-resistant GISTs might facilitate disease progression by promoting the malignant behavior of tumors in an FGF2-dependent manner. This provides a rationale to evaluate the effectiveness of the inhibitors of FGF-signaling for IM-resistant GISTs.

Angiogenesis in gastrointestinal stromal tumors: From bench to bedside

“…The FGF2/R2 signaling has been extensively studied in GIST as a drug resistance mechanism. Sergei et al [ 54 ] and Boichuk et al [ 55 ] demonstrated that the blockage of FGFR2 signaling could enhance the responsiveness to DNA-Topoisomerase II inhibitors[ 54 ] while the downregulation of FGF2 signaling might stimulate the response to imatinib[ 55 ]. It’s contribution in GIST progression has been reviewed[ 56 ] but data about potential effects in GIST vascularization process are missing.…”

Sensitive Metabolites and Single Nuclear Polymorphisms of OCT1 on Imatinib Meyslate in Patients with Gastrointestinal Stromal Tumors (GISTs)

“…However, the IM-resistance is the obstacle for trapping the further development of IM. Speci cally, more than 50% of patients with advanced and metastatic forms of the disease develop secondary resistance to IM-based therapy within 2 years after initiation of treatment [59]. It is widely known that IM is a successfully orally targeted drug, which metabolized by CYP 450 [60].…”

Improved understanding of gastrointestinal stromal tumors biology as a step for developing new diagnostic and therapeutic schemes (Review)

“…Massive secretion of the multiple chemokines, including FGF-2, was discovered to be induced by the imatinib c-KIT inhibition. Increased production of FGF-2 by GIST cells treated with imatinib activates the FGF-2/FGFR autocrine loop that presents a negative impact on the disease progression and might become one of the most important mechanisms underlying imatinib-resistance among some patients with GIST (30). Inhibition of FGF-signaling in imatinib-resistant patients was proved to restore their sensitivity to the applied treatment (31).…”