Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press80510.17650/2313-805X-2025-12-4-38-50REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИReview ArticleThe role of FGFR and VEGFR signaling pathways in the mechanisms of secondary resistance of gastrointestinal stromal tumors to tyrosine kinase receptor inhibitorsРоль FGFR- и VEGFR-сигнальных путей в механизмах вторичной резистентности гастроинтестинальных стромальных опухолей к ингибиторам тирозинкиназных рецепторовhttps://orcid.org/0000-0002-5449-4435DunaevP. D.ДунаевП. Д.
Russian Federation
boichuksergei@mail.ruhttps://orcid.org/0009-0004-9666-0130MukhutdinovaF. I.МухутдиноваФ. И.
Russian Federation
boichuksergei@mail.ruhttps://orcid.org/0009-0009-3945-8653ShashinaM. S.ШашинаМ. С.
Russian Federation
boichuksergei@mail.ruhttps://orcid.org/0000-0002-2078-4274KopninP. B.КопнинП. Б.
Russian Federation
boichuksergei@mail.ruhttps://orcid.org/0000-0003-2415-1084BoichukS. V.БойчукС. В.
Russian Federation
boichuksergei@mail.ruKazan State Medical University, Ministry of Health of RussiaФГБОУ ВО «Казанский государственный медицинский университет» Минздрава РоссииN.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава РоссииResearch Laboratory “Biomarker”, Institute of Fundamental Medicine and Biology of the Kazan Federal UniversityНаучно-исследовательская лаборатория «Биомаркер», Институт фундаментальной медицины и биологии ФГАОУ ВО «Казанский (Приволжский) федеральный университет»Russian Medical Academy of Continuing Professional Education, Ministry of Health of RussiaФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России1412202512438501508202525082025Copyright ©; 2025, Dunaev P.D., Mukhutdinova F.I., Shashina M.S., Kopnin P.B., Boichuk S.V.Copyright ©; 2025, Дунаев П.Д., Мухутдинова Ф.И., Шашина М.С., Копнин П.Б., Бойчук С.В.2025Dunaev P.D., Mukhutdinova F.I., Shashina M.S., Kopnin P.B., Boichuk S.V.Дунаев П.Д., Мухутдинова Ф.И., Шашина М.С., Копнин П.Б., Бойчук С.В.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/805

Currently, many scientific studies investigate the role of receptor tyrosine kinases in mechanisms of tumor cell resistance to targeted therapies and chemotherapies. Activation of FGFR and VEGR signaling pathways through fibroblast growth factors (FGF) and vascular endothelial growth factors (VEGF) is seen in many malignant neoplasms. The literature review was addressed to describe the role of FGFR and VEGFR signaling pathways in the secondary (acquired) resistance of gastrointestinal stromal tumors to the targeted drugs – tyrosine kinase receptor inhibitors (imatinib mesylate, sunitinib, regorafenib).

The review describes the molecular mechanisms of activation of FGFR and VEGR signaling pathways in tumor cells, as well as their structural and functional relationship between aforementioned pathways. Multiple studies, including our own, illustrate the activation of FGFR and VEGFR pathways in gastrointestinal stromal tumors. The review also describes the clinical effectiveness of FGFR and VEGFR inhibition for advanced and metastatic gastrointestinal stromal tumors, thereby providing a rationale to utilize activation of the aforementioned signaling pathways as the markers for gastrointestinal stromal tumors progression.

В настоящее время большое количество научных исследований посвящено изучению роли рецепторных тирозинкиназ в механизмах резистентности опухолевых клеток к таргетным и химиопрепаратам. Активация FGFR- и VEGR-сигнальных путей, запускаемых соответственно факторами роста фибробластов (FGF) и факторами роста эндотелия сосудов (VEGF), отмечается при развитии многих злокачественных новообразований.

Обзор литературы посвящен изучению роли сигналинга рецепторов FGF (FGFR) и VEGF (VEGFR) в развитии вторичной (приобретенной) резистентности гастроинтестинальных стромальных опухолей к таргетным препаратам – ингибиторам тирозинкиназных рецепторов (иматиниба мезилату, сунитинибу, регорафенибу). В статье представлена информация о механизмах активации FGFR- и VEGR-сигнальных путей в опухолевых клетках, а также об их структурной и функциональной взаимосвязи. Проведен анализ собственных исследований, посвященных изучению активации FGFR- и VEGFR-сигналинга в гастроинтестинальных стромальных опухолях. Описаны клинические испытания эффективности ингибиторов указанных сигнальных путей при диссеминированных формах этих новообразований, а также даны рекомендации по использованию маркеров активации FGFR- и VEGFR-сигналинга в диагностике прогрессирования гастроинтестинальных стромальных опухолей.

gastrointestinal stromal tumorimatinib resistancefibroblast growth factors receptorFGFR signaling pathwayvascular endothelial growth factors receptorVEGFR signaling pathwaytyrosine kinase receptor inhibitorsunitinibregorafenibгастроинтестинальная стромальная опухольрезистентность к иматинибусигнальный путь рецепторов факторов роста фибробластовFGFR-сигнальный путьсигнальный путь рецепторов факторов роста эндотелия сосудовVEGFR-сигнальный путьингибитор тирозинкиназных рецепторовсунитинибрегорафенибРоссийский научный фондRussian Science Foundation25-45-01008Российский научный Фонд (грант № 25-45-01008)Jakhetiya A., Garg P.K., Prakash G. et al. Targeted therapy of gastrointestinal stromal tumours. World J Gastrointest Surg 2016;8(5):345–52. DOI: 10.4240/wjgs.v8.i5.345Hirota S., Isozaki K., Moriyama Y. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279(5350):577–80. DOI: 10.1126/science.279.5350.577Sakurai S., Fukasawa T., Chong J.M. et al. C-kit gene abnormalities in gastrointestinal stromal tumors (tumors of interstitial cells of Cajal). Jpn J Cancer Res 1999;90(12):1321–8. DOI: 10.1111/j.1349-7006.1999.tb00715.xFu X., Wang X., Xiong J. et al. Surgical strategies for duodenal gastrointestinal stromal tumors. Langenbecks Arch Surg 2022;407(2):835–44. DOI: 10.1007/s00423-022-02460-5.Королева А.М., Когония Л.М. Вторая линия терапии гастроинтестинальных стромальных опухолей: ожидает ли нас выбор? Медицинский совет 2019;10:28–36. DOI: 10.21518/2079-701X-2019-10-28-36 Koroleva A.M., Kogonia L.M. Second line of therapy for gastrointestinal stromal tumors: is there a choice? Meditsinskiy sovet = Medical Council 2019;10:28–36. (In Russ.). DOI: 10.21518/2079-701X-2019-10-28-36Schaefer I.M., DeMatteo R.P., Serrano C. The GIST of advances in treatment of advanced gastrointestinal stromal tumor. Am Soc Clin Oncol Educ Book 2022;42:1–15. DOI: 10.1200/EDBK_351231Corless C.L., Heinrich M.C. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol 2008;3:557–86. DOI: 10.1146/annurev.pathmechdis.3.121806.151538Martín-Broto J., Rubio L., Alemany R. et al. Clinical implications of KIT and PDGFRA genotyping in GIST. Clin Transl Oncol 2010;12(10):670–6. DOI: 10.1007/s12094-010-0576-7Li J., Guo S., Sun Z. et al. Noncoding RNAs in drug resistance of gastrointestinal stromal tumor. Front Cell Dev Biol 2022;10:808591. DOI: 10.3389/fcell.2022.808591Liu P., Tan F., Liu H. et al. The use of molecular subtypes for precision therapy of recurrent and metastatic gastrointestinal stromal tumor. Onco Targets Ther 2020;13:2433–47. DOI: 10.2147/OTT.S241331Югай В.В., Никулин М.Р., Козлов Н.А. и др. Клинико-морфологические характеристики пациентов с гастроинтестинальной стромальной опухолью с дефицитом сукцинатдегидрогеназы. Вопросы онкологии 2022;68(5):614–21. DOI: 10.37469/0507-3758-2022-68-5-614-621 Yugai V.V., Nikulin M.R., Kozlov N.A. et al. Clinical and morphological characteristics of patients of gastrointestinal stromal tumor with deficiency of succinate dehydrogenase. Voprosy Onkologii = Oncology issues 2022;68(5):614–21. (In Russ.). DOI: 10.37469/0507-3758-2022-68-5-614-621Мазуренко Н.Н., Цыганова И.В. Молекулярно-генетические особенности и маркеры гастроинтестинальных стромальных опухолей. Успехи молекулярной онкологии 2015;2(2):29–40. DOI: 10.17650/2313-805X.2015.2.2.29-40 Mazurenko N.N., Tsyganova I.М. Molecular features and genetic markers of gastrointestinal stromal tumors. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2015;2(2):29–40. (In Russ.). DOI: 10.17650/2313-805X.2015.2.2.29-40Ibrahim A., Montgomery E.A. Gastrointestinal stromal tumors: variants and some pitfalls that they create. Adv Anat Pathol 2024;31(6):354–63. DOI: 10.1097/PAP.0000000000000463Gramza A.W., Corless C.L., Heinrich M.C. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res 2009;15(24):7510–8. DOI: 10.1158/1078-0432.CCR-09-0190Zhou S., Abdihamid O., Tan F. et al. KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST. Cell Commun Signal 2024;22(1):153. DOI: 10.1186/s12964-023-01411-xBoichuk S., Rausch J., Duensing A. New developments in management of gastrointestinal stromal tumors: regorafenib, the new player in the team. Gastrointestinal Cancer Targets Ther 2014;4:1–10. DOI: 10.2147/GICTT.S20679Blay J.Y., Kang Y.K., Nishida T. et al. Gastrointestinal stromal tumours. Nat Rev Dis Primers 2021;7(1):22. DOI: 10.1038/s41572-021-00254-5Kelly C.M., Gutierrez Sainz L., Chi P. The management of metastatic GIST: current standard and investigational therapeutics. J Hematol Oncol 2021;14(1):2. DOI: 10.1186/s13045-020-01026-6Clinical trials NCT03673501 – a study of ripretinib vs sunitinib in advanced gist patients after treatment with imatinib (INTRIGUE). Available at: https://clinicaltrials.gov/study/NCT03673501Strauss G., George S. Gastrointestinal stromal tumors. Curr Oncol Rep 2025;27(3):312–21. DOI: 10.1007/s11912-025-01636-8Takahashi T., Serada S., Ako M. et al. New findings of kinase switching in gastrointestinal stromal tumor under imatinib using phosphoproteomic analysis. Int J Cancer 2013;133(11):2737–43. DOI: 10.1002/ijc.28282Fu J., Su X., Li Z. et al. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene 2021;40(28):4625–51. DOI: 10.1038/s41388-021-01863-wPeng M., Li H., Cao H. et al. Dual FGFR and VEGFR inhibition synergistically restrain hexokinase 2-dependent lymphangiogenesis and immune escape in intrahepatic cholangiocarcinoma. J Gastroenterol 2023;58(9):908–24. DOI: 10.1007/s00535-023-02012-8Fukumura D., Kloepper J., Amoozgar Z. et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018;15(5):325–40. DOI: 10.1038/nrclinonc.2018.29Miao J.L., Zhou J.H., Cai J.J. et al. The association between fibroblast growth factor receptor 1 gene amplification and lung cancer: a meta-analysis. Arch Med Sci 2019;16(1):16–26. DOI: 10.5114/aoms.2020.91284Pecqueux C., Arslan A., Heller M. et al. FGF-2 is a driving force for chromosomal instability and a stromal factor associated with adverse clinico-pathological features in prostate cancer. Urol Oncol 2018;36(8):365.e15–365.e26. DOI: 10.1016/j.urolonc.2018.05.020Clark J.F., Soriano P. FRS2-independent GRB2 interaction with FGFR2 is not required for embryonic development. Biol Open 2023;12(7):bio059942. DOI: 10.1242/bio.059942Xie Y., Su N., Yang J. et al. FGF/FGFR signaling in health and disease. Signal Transduct Target Ther 2020;5(1):181. DOI: 10.1038/s41392-020-00222-7Gędaj A., Gregorczyk P., Żukowska D. et al. Glycosylation of FGF/FGFR: an underrated sweet code regulating cellular signaling programs. Cytokine Growth Factor Rev 2024;77:39–55. DOI: 10.1016/j.cytogfr.2024.04.001Ornitz D.M., Itoh N. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol 2015;4(3):215–66. DOI: 10.1002/wdev.176Katoh M., Nakagama H. FGF receptors: cancer biology and therapeutics. Med Res Rev 2014;34(2):280–300. DOI: 10.1002/med.21288Helsten T., Elkin S., Arthur E. et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res 2016;22(1):259–67. DOI: 10.1158/1078-0432.CCR-14-3212Zhang P., Yue L., Leng Q. et al. Targeting FGFR for cancer therapy. J Hematol Oncol 2024;17(1):39. DOI: 10.1186/s13045-024-01558-1Федянин М.Ю., Хмелькова Д.Н., Серебрийская Т.С. и др. Перспективы терапевтического воздействия на сигнальный путь FGFR. Успехи молекулярной онкологии 2015;2(1):27–38. DOI: 10.17650/2313-805X.2015.2.1.027-038 Fedyanin M.Yu., Khmelkova D.N., Serebriyskaya T.S. et al. Prospects of therapeutic action on FGFR signaling pathway. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2015;2(1):27–38. (In Russ.). DOI: 10.17650/2313-805X.2015.2.1.027-038Федянин М.Ю., Хмелькова Д.Н., Серебрийская Т.С. и др. Рецепторы фактора роста фибробластов при злокачественных опухолях. Злокачественные опухоли 2014;(4):19–34. DOI: 10.18027/2224-5057-2014-4-19-34 Fedyanin M.Yu., Hmel’kova D.N., Serebriyskaya T.S. et al. Fibroblast growth factor receptors in malignant tumors. Zlokachestvennye opukholi = Malignant Tumours 2014;(4):19–34. (In Russ.). DOI: 10.18027/2224-5057-2014-4-19-34De Luca A., Esposito Abate R., Rachiglio A.M. et al. FGFR fusions in cancer: from diagnostic approaches to therapeutic intervention. Int J Mol Sci 2020;21(18):6856. DOI: 10.3390/ijms21186856Liu G., Chen T., Ding Z. et al. Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment. Cell Prolif 2021;54(4):e13009. DOI: 10.1111/cpr.13009Wang Z., Anderson K.S. Therapeutic targeting of FGFR signaling in head and neck cancer. Cancer J 2022;28(5):354–62. DOI: 10.1097/PPO.0000000000000615Chudasama P., Renner M., Straub M. et al. Targeting fibroblast growth factor receptor 1 for treatment of soft-tissue sarcoma. Clin Cancer Res 2017;23(4):962–73. DOI: 10.1158/1078-0432.CCR-16-0860Kawamata F., Patch A.M., Nones K. et al. Copy number profiles of paired primary and metastatic colorectal cancers. Oncotarget 2017;9(3):3394–405. DOI: 10.18632/oncotarget.23277Turner N., Lambros M.B., Horlings H.M. et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene 2010;29(14):2013–23. DOI: 10.1038/onc.2009.489Catenacci D.V., Tesfaye A., Tejani M. et al. Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT phase III study design. Future Oncol 2019;15(18):2073–82. DOI: 10.2217/fon-2019-0141Facchinetti F., Loriot Y., Brayé F. et al. Understanding and overcoming resistance to selective FGFR inhibitors across FGFR2-driven malignancies. Clin Cancer Res 2024;30(21): 4943–56. DOI: 10.1158/1078-0432.CCR-24-1834Koole K., van Kempen P.M., Swartz J.E. et al. Fibroblast growth factor receptor 3 protein is overexpressed in oral and oropharyngeal squamous cell carcinoma. Cancer Med 2016;5(2):275–84. DOI: 10.1002/cam4.595Fromme J.E., Schmitz K., Wachter A. et al. FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis. Oncotarget 2018;9(63):32204–18. DOI: 10.18632/oncotarget.25941Mahipal A., Tella S.H., Kommalapati A. et al. FGFR2 genomic aberrations: achilles heel in the management of advanced cholangiocarcinoma. Cancer Treat Rev 2019;78:1–7. DOI: 10.1016/j.ctrv.2019.06.003Ho H.K., Pok S., Streit S. et al. Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention. J Hepatol 2009;50(1):118–27. DOI: 10.1016/j.jhep.2008.08.015Li X., Wang C., Xiao J. et al. Fibroblast growth factors, old kids on the new block. Semin Cell Dev Biol 2016;53:155–67. DOI: 10.1016/j.semcdb.2015.12.014Korc M., Friesel R.E. The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets 2009;9(5):639–51. DOI: 10.2174/156800909789057006Wang K., Ji W., Yu Y. et al. FGFR1-ERK1/2-SOX2 axis promotes cell proliferation, epithelial-mesenchymal transition, and metastasis in FGFR1-amplified lung cancer. Oncogene 2018;37(39):5340–54. DOI: 10.1038/s41388-018-0311-3Santolla M.F., Vivacqua A., Lappano R. et al. GPER mediates a feedforward FGF2/FGFR1 paracrine activation coupling CAFs to cancer cells toward breast tumor progression. Cells 2019;8(3):223. DOI: 10.3390/cells8030223Knuchel S., Anderle P., Werfelli P. et al. Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion. Oncotarget 2015;6(16):14300–17. DOI: 10.18632/oncotarget.3883Song S., Wientjes M.G., Gan Y. et al. Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs. Proc Natl Acad Sci USA 2000;97(15):8658–63. DOI: 10.1073/pnas.140210697Liu D., Liu H., Gan J. et al. LY2874455 and abemaciclib reverse FGF3/4/19/CCND1 amplification mediated gefitinib resistance in NSCLC. Front Pharmacol 2022;13:918317. DOI: 10.3389/fphar.2022.918317Menzel T., Rahman Z., Calleja E. et al. Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine. Blood 1996;87(3):1056–63.Szerlip N.J., Pedraza A., Chakravarty D. et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci USA 2012;109(8):3041–6. DOI: 10.1073/pnas.1114033109.Ruotsalainen T., Joensuu H., Mattson K. et al. High pretreatment serum concentration of basic fibroblast growth factor is a predictor of poor prognosis in small cell lung cancer. Cancer Epidemiol Biomarkers Prev 2002;11(11):1492–5.Salven P., Orpana A., Teerenhovi L. et al. Simultaneous elevation in the serum concentrations of the angiogenic growth factors VEGF and bFGF is an independent predictor of poor prognosis in non-Hodgkin lymphoma: a single-institution study of 200 patients. Blood 2000;96(12):3712–8.Álvarez-Aznar A., Muhl L., Gaengel K. VEGF receptor tyrosine kinases: key regulators of vascular function. Curr Top Dev Biol 2017;123:433–482. DOI: 10.1016/bs.ctdb.2016.10.001Wiszniak S., Schwarz Q. Exploring the intracrine functions of VEGF-A. Biomolecules 2021;11(1):128. DOI: 10.3390/biom11010128Mac Gabhann F., Popel A.S. Dimerization of VEGF receptors and implications for signal transduction: a computational study. Biophys Chem 2007;128(2-3):125–39. DOI: 10.1016/j.bpc.2007.03.010Simons M., Gordon E., Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 2016;17(10):611–25. DOI: 10.1038/nrm.2016.87Leppänen V.M., Tvorogov D., Kisko K. et al. Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc Natl Acad Sci USA 2013;110(32):12960–5. DOI: 10.1073/pnas.1301415110Olsson A.K., Dimberg A., Kreuger J. et al. VEGF receptor signalling – in control of vascular function. Nat Rev Mol Cell Biol 2006;7(5):359–71. DOI: 10.1038/nrm1911Бабышкина Н.Н., Завьялова М.В., Брагина О.Д. и др. Оценка предсказательной значимости рецептора сосудистого эндотелиального фактора роста VEGFR-2 у больных тройным негативным раком молочной железы. Сибирский онкологический журнал 2016;15(5):9–17. DOI: 10.21294/1814-4861-2016-15-5-9-17 Babyshkina N.N., Zavyalova M.V., Bragina O.D. et al. Predictive significance of vascular endothelial growth factor receptor VEGF-2 in triple-negative breast cancer patients. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology 2016;15(5):9–17. (In Russ.). DOI: 10.21294/1814-4861-2016-15-5-9-17Корчагина А.А., С. Шеин С.А., Гурина О.И. и др. Роль рецепторов VEGFR в неопластическом ангиогенезе и перспективы терапии опухолей мозга. Вестник Российской академии медицинских наук 2013;68(11):104–14. DOI: 10.15690/vramn.v68i11.851 Korchagina A.A., Shein S.A., Gurina O.I. et al. VEGFRS in neoplastic angiogenesis and prospects for therapy оf brain tumors. Vestnik Rossiyskoy akademii meditsinskikh nauk = Annals of the Russian Academy of Medical Sciences 2013;68(11):104–14. (In Russ.). DOI: 10.15690/vramn.v68i11.851Palazon A., Tyrakis P.A., Macias D. et al. An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell 2017;32(5):669–83.e5. DOI: 10.1016/j.ccell.2017.10.003Mabeta P., Steenkamp V. The VEGF/VEGFR axis revisited: implications for cancer therapy. Int J Mol Sci 2022;23(24):15585. DOI: 10.3390/ijms232415585Lorenc P., Sikorska A., Molenda S. et al. Physiological and tumor-associated angiogenesis: key factors and therapy targeting VEGF/VEGFR pathway. Biomed Pharmacother 2024;180:117585. DOI: 10.1016/j.biopha.2024.117585Apte R.S., Chen D.S., Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell 2019;176(6):1248–64. DOI: 10.1016/j.cell.2019.01.021Ghalehbandi S., Yuzugulen J., Pranjol M.Z.I. et al. The role of VEGF in cancer-induced angiogenesis and research progress of drugs targeting VEGF. Eur J Pharmacol 2023;949:175586. DOI: 10.1016/j.ejphar.2023.175586McAuliffe J.C., Lazar A.J., Yang D. et al. Association of intratumoral vascular endothelial growth factor expression and clinical outcome for patients with gastrointestinal stromal tumors treated with imatinib mesylate. Clin Cancer Res 2007;13(22 Pt 1):6727–34. DOI: 10.1158/1078-0432.CCR-07-0895Imamura M., Yamamoto H., Nakamura N. et al. Prognostic significance of angiogenesis in gastrointestinal stromal tumor. Mod Pathol 2007;20(5):529–37. DOI: 10.1038/modpathol.3800767Golfmann K., Meder L., Koker M. et al. Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1-amplified breast cancer. Oncogene 2018;37(42):5682–93. DOI: 10.1038/s41388-018-0380-3Murakami M., Nguyen L.T., Hatanaka K. et al. FGF-dependent regulation of VEGF receptor 2 expression in mice. J Clin Invest 2011;121(7):2668–78. DOI: 10.1172/JCI44762Xue L., Greisler H.P. Angiogenic effect of fibroblast growth factor-1 and vascular endothelial growth factor and their synergism in a novel in vitro quantitative fibrin-based 3-dimensional angiogenesis system. Surgery 2002;132(2):259–67. DOI: 10.1067/msy.2002.125720Ichikawa K., Watanabe Miyano S., Minoshima Y. et al. Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy. Sci Rep 2020;10(1):2939. DOI: 10.1038/s41598-020-59853-zDeng H., Kan A., Lyu N. et al. Dual vascular endothelial growth factor receptor and fibroblast growth factor receptor inhibition elicits antitumor immunity and enhances programmed cell death-1 checkpoint blockade in hepatocellular carcinoma. Liver Cancer 2020;9(3):338–57. DOI: 10.1159/000505695Glabman R.A., Choyke P.L., Sato N. Cancer-associated fibroblasts: tumorigenicity and targeting for cancer therapy. Cancers 2022;14(16):3906. DOI: 10.3390/cancers14163906Yang J., Yan J., Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol 2018;9:978. DOI: 10.3389/fimmu.2018.00978Chen P.Y., Qin L., Zhuang Z.W. et al. The docking protein FRS2α is a critical regulator of VEGF receptors signaling. Proc Natl Acad Sci USA 2014;111(15):5514–9. DOI: 10.1073/pnas.1404545111Li F., Huynh H., Li X. et al. FGFR-mediated reactivation of MAPK signaling attenuates antitumor effects of imatinib in gastrointestinal stromal tumors. Cancer Discov 2015;5(4):438–51. DOI: 10.1158/2159-8290.CD-14-0763Javidi-Sharifi N., Traer E., Martinez J. et al. Crosstalk between KIT and FGFR3 promotes gastrointestinal stromal tumor cell growth and drug resistance. Cancer Res 2015;75(5):880–91. DOI: 10.1158/0008-5472.CAN-14-0573Дунаев П.Д., Бойчук С.В., Галембикова А.Р. и др. Получение иматиниб-резистентного субклона клеток гастроинтестинальной стромальной опухоли и исследование его чувствительности к химиопрепаратам. Казанский медицинский журнал 2017;98(6):993–7. DOI: 10.17750/KMJ2017-993 Dunaev P.D., Boichuk S.V., Galembikova A.R. et al. Establishment of imatinib-resistant gastrointestinal stromal tumor cell subline and investigation of its sensitivity to the chemomotherapeutic agents. Kazanskiy medicinskiy zhurnal = Kazan Medical Journal 2017;98(6):993–7. (In Russ.). DOI: 10.17750/KMJ2017-993Boichuk S., Galembikova A., Dunaev P. et al. A novel receptor tyrosine kinase switch promotes gastrointestinal stromal tumor drug resistance. Molecules 2017;22(12):2152. DOI: 10.3390/molecules22122152Boichuk S., Dunaev P., Galembikova A. et al. Fibroblast growth factor 2 (FGF2) activates vascular endothelial growth factor (VEGF) signaling in gastrointestinal stromal tumors (GIST): an autocrine mechanism contributing to imatinib mesylate (IM) resistance. Cancers 2024;16(17):3103. DOI: 10.3390/cancers16173103Boichuk S., Galembikova A., Mikheeva E. et al. Inhibition of FGF2-mediated signaling in GIST-promising approach for overcoming resistance to imatinib. Cancers 2020;12(6):1674. DOI: 10.3390/cancers12061674Boichuk S., Galembikova A., Dunaev P. et al. Targeting of FGF-signaling re-sensitizes gastrointestinal stromal tumors (GIST) to imatinib in vitro and in vivo. Molecules 2018;23(10):2643. DOI: 10.3390/molecules23102643Boichuk S., Dunaev P., Skripova V. et al. Unraveling the mechanisms of sensitivity to anti-FGF therapies in imatinib-resistant gastrointestinal stromal tumors (GIST) lacking secondary KIT mutations. Cancers 2023;15(22):5354. DOI: 10.3390/cancers15225354Clinical trials NCT02257541 – BGJ398 in combination with imatinib mesylate in patients with untreated advanced gastrointestinal stromal tumor (GIST). Available at: https://clinicaltrials.gov/study/NCT02257541?cond=GIST%20-%20Gastrointestinal%20Stromal%20Tumor&intr=Infigratinib&rank=1Schöffski P., Mir O., Kasper B. et al. Activity and safety of the multi-target tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 ‘CaboGIST’. Eur J Cancer 2020;134;62–74. DOI: 10.1016/j.ejca.2020.04.021Cai Z., Chen X., Zhang B. et al. Apatinib treatment in metastatic gastrointestinal stromal tumor. Front Oncol 2019;9:470. DOI: 10.3389/fonc.2019.00470Xu H., Zhou S., Hu Q. et al. Apatinib treatment for unresectable gastrointestinal stromal tumor with synchronous gastric cancer. Precis Clin Med 2020;3(1):67–70. DOI: 10.1093/pcmedi/pbaa005Clinical trials NCT05751733 – apatinib mesylate versus standard second-line TKI in the treatment of advanced GIST. Available at: https://clinicaltrials.gov/study/NCT05751733Blanke C.D., Rankin C., Corless C. et al. S0502: a SWOG phase III randomized study of imatinib, with or without bevacizumab, in patients with untreated metastatic or unresectable gastrointestinal stromal tumors. Oncologist 2015;20(12):1353–4. DOI: 10.1634/theoncologist.2015-0295Clinical trials NCT01363024 – trial evaluating the safety and pharmacokinetics of MFGR1877S in patients with advanced solid tumors. Available at: https://clinicaltrials.gov/study/NCT01363024Babina I.S., Turner N.C. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer 2017;17(5):318–32. DOI: 10.1038/nrc.2017.8Xiang H., Liu L., Gao Y. et al. Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial. Cancer Chemother Pharmacol 2020;86(5):595–606. DOI: 10.1007/s00280-020-04139-4Schöffski P., Gebreyohannes Y., Van Looy T. et al. In vivo evaluation of fibroblast growth factor receptor inhibition in mouse xenograft models of gastrointestinal stromal tumor. Biomedicines 2022;10(5):1135. DOI: 10.3390/biomedicines10051135Clinical trials NCT02268435 – dovitinib in combination with imatinib in patients with gastrointestinal stromal tumors. Available at: https://clinicaltrials.gov/study/NCT02268435?a=1Shen G., Zheng F., Ren D. et al. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol 2018;11(1):120. DOI: 10.1186/s13045-018-0664-7Zhou Y., Zeng C., Sun X. et al. Activity of anlotinib in the second-line therapy of metastatic gastrointestinal stromal tumors: a prospective, multicenter, in vitro study. Oncologist 2023;28(4):e191–7. DOI: 10.1093/oncolo/oyac271Clinical trials NCT04193553 – multicentre placebo-controlled double-blinded phase II study of lenvatinib efficacy in patients with locally advanced or metastatic GIST (gastrointestinal stromal tumor) after imatinib/sunitinib failure (LENVAGIST). Available at: https://clinicaltrials.gov/study/ NCT04193553#study-overview