Inhibition of fibroblast growth factor receptor-signaling sensitizes imatinib-resistant gastrointestinal stromal tumors to low doses of topoisomerase II inhibitors

Boichuk, Sergei; Dunaev, Pavel; Galembikova, Aigul; Мустафин, И Г; Valeeva, Elena V.

doi:10.1097/cad.0000000000000637

Cited by 12 publications

(13 citation statements)

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“…For example, we showed that IM-resistant GIST cell lines established in our lab harbored a receptor-tyrosine kinase (RTK) switch (loss of c-KIT/gain of FGFR2), thus revealing the possibility of FGFR activation after prolonged IM exposure [ 21 ]. Moreover, we observed that aberrant FGFR signaling in IM-resistant GIST cells has an impact on GIST resistance to IM and topoisomerase II inhibitors [ 21 , 22 ]. The latter might be due to the ability of FGFR signaling to maintain effective repair of DNA double-strand breaks (DSBs) via a homology-mediated pathway [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo

et al. 2018

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Dysregulation of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling pathway is frequently observed in multiple human malignancies, and thus, therapeutic strategies targeting FGFs and FGFRs in human cancer are being extensively explored. We observed the activation of the FGF/FGFR-signaling pathway in imatinib (IM)-resistant gastrointestinal stromal tumor (GIST) cells. Furthermore, we found that the activation of FGFR signaling has a significant impact on IM resistance in GISTs in vitro. Next, we tested the efficacy of BGJ398, a potent and selective FGFR1–3 inhibitor, in xenograft models of GISTs exhibiting secondary IM resistance due to receptor-tyrosine kinase (RTK) switch (loss of c-KIT/gain of FGFR2a). Five to eight-week-old female nu/nu mice were subcutaneously inoculated into the flank areas with GIST T-1R cells. Mice were randomized as control (untreated), IM, BGJ398, or a combination and treated orally for 12 days. IM had a moderate effect on tumor size, thus revealing GIST resistance to IM. Similarly, a minor regression in tumor size was observed in BGJ398-treated mice. Strikingly, a 90% decrease in tumor size was observed in mice treated with a combination of IM and BGJ398. Treatment with BGJ398 and IM also induced major histopathologic changes according to a previously defined histopathologic response score and resulted in massive myxoid degeneration. This was associated with increased intratumoral apoptosis as detected by immunohistochemical staining for cleaved caspase-3 on day 5 of the treatment. Furthermore, treatment with BGJ398 and IM significantly reduced the proliferative activity of tumor cells as measured by positivity for Ki-67 staining. In conclusion, inhibition of FGFR signaling substantially inhibited the growth of IM-resistant GISTs in vitro and showed potent antitumor activity in an IM-resistant GIST model via the inhibition of proliferation, tumor growth, and the induction of apoptosis, thereby suggesting that patients with advanced and metastatic GISTs exhibiting IM resistance might benefit from therapeutic inhibition of FGFR signaling.

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Section: Introductionmentioning

confidence: 99%

“…Moreover, we observed that aberrant FGFR signaling in IM-resistant GIST cells has an impact on GIST resistance to IM and topoisomerase II inhibitors [ 21 , 22 ]. The latter might be due to the ability of FGFR signaling to maintain effective repair of DNA double-strand breaks (DSBs) via a homology-mediated pathway [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo

et al. 2018

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“…Moreover, BGJ398, a selective FGFR1-3 inhibitor, has a high potency to sensitize IM-resistant GIST cells to the topoisomerase II inhibitors, doxorubicin and etoposide. A substantial decrease of cell viability, proliferation and growth was found in IM-resistant GIST cells simultaneously treated with FGFR-and DNA-topoisomerase II inhibitors [18]. Based on this data, we wondered whether inhibition of FGFRsignaling might have an impact on DNA damage signaling and repair in GIST cells, especially on tumor cells that acquired IM-resistant phenotype over IM-based therapy.…”

Section: Discussionmentioning

confidence: 99%

“…It was shown previously that GIST cell lines and patient-derived IM-resistant primary GIST cells are sensitive to certain chemotherapeutic agents, such as topoisomerase II inhibitors and transcriptional inhibitors [19,20]. Based on our previous data illustrating that inhibition of FGF-signaling in GIST effectively sensitized them to DNA damaging agents (e.g., topoisomerase II inhibitors) [18], we sought to examine whether it might be due to decreased efficiency of DDR mechanisms involved in repair of the double-strand breaks (DSBs).…”

Section: Fgfr Inhibition Delays Dna Dsbs Repair Im-resistant Gistsmentioning

confidence: 94%

“…We also observed that inhibition of FGFR signaling in IM-resistant GIST cells sensitizes them to DNA damaging agents, such as topoisomerase II inhibitors. Importantly, when FGFR2 was knocked down by siRNA and/or inhibited with BGJ398, a selective FGFR1-4 inhibitor, IM-resistant GIST cells exhibited a reduced level of Rad51 recombinase after doxorubicin exposure, thus suggesting the attenuation of homology-mediated DNA repair mechanisms [18].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of FGFR2-Signaling Attenuates a Homology-Mediated DNA Repair in GIST and Sensitizes Them to DNA-Topoisomerase II Inhibitors

Boichuk

Dunaev

Galembikova

et al. 2020

IJMS

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Deregulation of receptor tyrosine kinase (RTK)-signaling is frequently observed in many human malignancies, making activated RTKs the promising therapeutic targets. In particular, activated RTK-signaling has a strong impact on tumor resistance to various DNA damaging agents, e.g., ionizing radiation and chemotherapeutic drugs. We showed recently that fibroblast growth factor receptor (FGFR)-signaling might be hyperactivated in imatinib (IM)-resistant gastrointestinal stromal tumors (GIST) and inhibition of this pathway sensitized tumor cells to the low doses of chemotherapeutic agents, such as topoisomerase II inhibitors. Here, we report that inhibition of FGFR-signaling in GISTs attenuates the repair of DNA double-strand breaks (DSBs), which was evidenced by the delay in γ-H2AX decline after doxorubicin (Dox)-induced DNA damage. A single-cell gel electrophoresis (Comet assay) data showed an increase of tail moment in Dox-treated GIST cells cultured in presence of BGJ398, a selective FGFR1-4 inhibitor, thereby revealing the attenuated DNA repair. By utilizing GFP-based reporter constructs to assess the efficiency of DSBs repair via homologous recombination (HR) and non-homologous end-joining (NHEJ), we found for the first time that FGFR inhibition in GISTs attenuated the homology-mediated DNA repair. Of note, FGFR inhibition/depletion did not reduce the number of BrdU and phospho-RPA foci in Dox-treated cells, suggesting that inhibition of FGFR-signaling has no impact on the processing of DSBs. In contrast, the number of Dox-induced Rad51 foci were decreased when FGFR2-mediated signaling was interrupted/inhibited by siRNA FGFR2 or BGJ398. Moreover, Rad51 and -H2AX foci were mislocalized in FGFR-inhibited GIST and the amount of Rad51 was substantially decreased in -H2AX-immunoprecipitated complexes, thereby illustrating the defect of Rad51 recombinase loading to the Dox-induced DSBs. Finally, as a result of the impaired homology-mediated DNA repair, the increased numbers of hypodiploid (i.e., apoptotic) cells were observed in FGFR2-inhibited GISTs after Dox treatment. Collectively, our data illustrates for the first time that inhibition of FGF-signaling in IM-resistant GIST interferes with the efficiency of DDR signaling and attenuates the homology-mediated DNA repair, thus providing the molecular mechanism of GIST’s sensitization to DNA damaging agents, e.g., DNA-topoisomerase II inhibitors.

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Molecular-Genetic Basis of Gastrointestinal Stromal Tumor Personalized Therapy by Receptor Tyrosine Kinase Inhibitors (A Review)

et al. 2021

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Inhibition of fibroblast growth factor receptor-signaling sensitizes imatinib-resistant gastrointestinal stromal tumors to low doses of topoisomerase II inhibitors

Cited by 12 publications

References 40 publications

Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo

Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo

Inhibition of FGFR2-Signaling Attenuates a Homology-Mediated DNA Repair in GIST and Sensitizes Them to DNA-Topoisomerase II Inhibitors

Molecular-Genetic Basis of Gastrointestinal Stromal Tumor Personalized Therapy by Receptor Tyrosine Kinase Inhibitors (A Review)

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