Abstract
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.
Highlights
Fibroblast growth factors (FGFs) and their receptors (FGFR1–4) are ubiquitously expressed in human tissues and regulate a broad spectrum of physiologic processes including embryonic and tissue development, differentiation, proliferation, survival, migration, and angiogenesis
This data suggests that the activation of FGF/fibroblast growth factor receptor (FGFR) signaling might be responsible for IM resistance in gastrointestinal stromal tumor (GIST) [21]
We found that IM-resistant GIST cells exhibited a coordinated activation of receptor-tyrosine kinase (RTK) involved in FGFR-signaling pathways—RAS-MAPK and PI3K-AKT
Summary
Fibroblast growth factors (FGFs) and their receptors (FGFR1–4) are ubiquitously expressed in human tissues and regulate a broad spectrum of physiologic processes including embryonic and tissue development, differentiation, proliferation, survival, migration, and angiogenesis. Dysregulation of FGF/FGFR signaling pathways is frequently observed in human cancer and has been documented for melanoma, hepatocellular carcinoma, breast, bladder, endometrial, head and neck, prostate, and lung cancers [1,2,3]. Molecules 2018, 23, 2643 human cancers include the following: (i) FGFR-activating point mutations that promote dimerization or enhance kinase activity. Of non-muscle, invasive urothelial carcinomas [4], whereas missense activating mutations of the extracellular domain in FGFR2 are documented in 12% to 14% of endometrial cancer cases [5,6];. FGFR1 amplification has been found in up to 20% of squamous non-small cell lung carcinomas (NSCLC), 18% of osteosarcomas, 10% of breast carcinomas, and 6% of small cell lung carcinomas [7,8,9], and was associated with sensitivity to FGFR inhibitors in preclinical in vivo models.
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