Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo
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 o...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2018-10-01
|
Series: | Molecules |
Subjects: | |
Online Access: | http://www.mdpi.com/1420-3049/23/10/2643 |
id |
doaj-57fcc37f994348e583c28a8cad12385e |
---|---|
record_format |
Article |
spelling |
doaj-57fcc37f994348e583c28a8cad12385e2020-11-24T21:28:03ZengMDPI AGMolecules1420-30492018-10-012310264310.3390/molecules23102643molecules23102643Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In VivoSergei Boichuk0Aigul Galembikova1Pavel Dunaev2Ekaterina Micheeva3Elena Valeeva4Maria Novikova5Natalya Khromova6Pavel Kopnin7Department of Pathology, Kazan State Medical University, Kazan 420012, RussiaDepartment of Pathology, Kazan State Medical University, Kazan 420012, RussiaDepartment of Pathology, Kazan State Medical University, Kazan 420012, RussiaDepartment of Pathology, Kazan State Medical University, Kazan 420012, RussiaDepartment of Pathology, Kazan State Medical University, Kazan 420012, RussiaN.N. Blokhin National Medical Research Center of Oncology, Moscow 115478, RussiaN.N. Blokhin National Medical Research Center of Oncology, Moscow 115478, RussiaN.N. Blokhin National Medical Research Center of Oncology, Moscow 115478, RussiaDysregulation 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.http://www.mdpi.com/1420-3049/23/10/2643gastrointestinal stromal tumor cells (GIST)imatinib (IM)resistanceFGFR signaling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sergei Boichuk Aigul Galembikova Pavel Dunaev Ekaterina Micheeva Elena Valeeva Maria Novikova Natalya Khromova Pavel Kopnin |
spellingShingle |
Sergei Boichuk Aigul Galembikova Pavel Dunaev Ekaterina Micheeva Elena Valeeva Maria Novikova Natalya Khromova Pavel Kopnin Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo Molecules gastrointestinal stromal tumor cells (GIST) imatinib (IM) resistance FGFR signaling |
author_facet |
Sergei Boichuk Aigul Galembikova Pavel Dunaev Ekaterina Micheeva Elena Valeeva Maria Novikova Natalya Khromova Pavel Kopnin |
author_sort |
Sergei Boichuk |
title |
Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo |
title_short |
Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo |
title_full |
Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo |
title_fullStr |
Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo |
title_full_unstemmed |
Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo |
title_sort |
targeting of fgf-signaling re-sensitizes gastrointestinal stromal tumors (gist) to imatinib in vitro and in vivo |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2018-10-01 |
description |
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. |
topic |
gastrointestinal stromal tumor cells (GIST) imatinib (IM) resistance FGFR signaling |
url |
http://www.mdpi.com/1420-3049/23/10/2643 |
work_keys_str_mv |
AT sergeiboichuk targetingoffgfsignalingresensitizesgastrointestinalstromaltumorsgisttoimatinibinvitroandinvivo AT aigulgalembikova targetingoffgfsignalingresensitizesgastrointestinalstromaltumorsgisttoimatinibinvitroandinvivo AT paveldunaev targetingoffgfsignalingresensitizesgastrointestinalstromaltumorsgisttoimatinibinvitroandinvivo AT ekaterinamicheeva targetingoffgfsignalingresensitizesgastrointestinalstromaltumorsgisttoimatinibinvitroandinvivo AT elenavaleeva targetingoffgfsignalingresensitizesgastrointestinalstromaltumorsgisttoimatinibinvitroandinvivo AT marianovikova targetingoffgfsignalingresensitizesgastrointestinalstromaltumorsgisttoimatinibinvitroandinvivo AT natalyakhromova targetingoffgfsignalingresensitizesgastrointestinalstromaltumorsgisttoimatinibinvitroandinvivo AT pavelkopnin targetingoffgfsignalingresensitizesgastrointestinalstromaltumorsgisttoimatinibinvitroandinvivo |
_version_ |
1725971868620423168 |