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Open AccessArticle

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

1
Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia
2
Central Research Laboratory, Kazan State Medical University, 420012 Kazan, Russia
3
Tatarstan Cancer Center, 420029 Kazan, Russia
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Department of Electron Microscopy, A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
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V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, 117997 Moscow, Russia
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Department of Mathematical Methods in Biology, A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
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Oncogenomics Laboratory, Carcinogenesis Institute, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
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Cytogenetics Laboratory, Carcinogenesis Institute, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1674; https://doi.org/10.3390/cancers12061674
Received: 25 April 2020 / Revised: 12 June 2020 / Accepted: 18 June 2020 / Published: 24 June 2020
(This article belongs to the Special Issue Management of Soft Tissue Sarcomas and GIST)
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. View Full-Text
Keywords: gastrointestinal stromal tumors (GISTs); imatinib (IM); sunitinib (SU); resistance; receptor tyrosine kinase (RTK); c-KIT and FGFR-signaling; FGF-2; autocrine pathway gastrointestinal stromal tumors (GISTs); imatinib (IM); sunitinib (SU); resistance; receptor tyrosine kinase (RTK); c-KIT and FGFR-signaling; FGF-2; autocrine pathway
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Boichuk, S.; Galembikova, A.; Mikheeva, E.; Bikinieva, F.; Aukhadieva, A.; Dunaev, P.; Khalikov, D.; Petrov, S.; Kurtasanov, R.; Valeeva, E.; Kireev, I.; Dugina, V.; Lushnikova, A.; Novikova, M.; Kopnin, P. Inhibition of FGF2-Mediated Signaling in GIST—Promising Approach for Overcoming Resistance to Imatinib. Cancers 2020, 12, 1674.

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