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.

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In this review presented the most relevant scientific information on the molecular and genetic features of gastrointestinal stromal tumors (GISTs). GISTs is a heterogeneous group of mesenchymal neoplasms of the gastrointestinal tract, which according to modern ideas originate from the interstitial cells of Cajal. It was found that this disease is largely somatic mutations: in the overwhelming majority of cases, activating mutations in kit or PDGFRA genes that encode effector tyrosine kinases are found in tumor cells. Constitutive activation of these enzymes triggers a complex cascade of intracellular reactions, the result of which is the enhancement of cell proliferation and tumor growth. In the absence of the above-mentioned driver mutations, the GISTs is referred to as a “wild type”. The profile of mutations affects the aggressiveness of the GISTs flow and the sensitivity to target antitumor drugs. Thus, carrying out a mutational analysis in the case of a GISTs is of great prognostic significance.