BGJ398, A Pan-FGFR Inhibitor, Overcomes Paclitaxel Resistance in Urothelial Carcinoma with FGFR1 Overexpression.
Se Hyun KimHaram RyuChan-Young OckKoung Jin SuhJi Yun LeeJi-Won KimJeong-Ok LeeJin Won KimYu Jung KimKeun-Wook LeeSoo-Mee BangJee Hyun KimJong Seok LeeJoong Bae AhnKui-Jin KimSun Young RhaPublished in: International journal of molecular sciences (2018)
Paclitaxel (PTX) is commonly used to treat urothelial carcinoma (UC) after platinum-based chemotherapy has failed. However, single-agent taxane therapy is not sufficient to inhibit tumor progression and drug resistance in advanced UC. Epithelial-to-mesenchymal transition (EMT) induced by fibroblast growth factor receptor (FGFR)1 signaling has been proposed as a mechanism of PTX resistance, but it is unclear whether this can be overcome by FGFR1 inhibition. The present study investigated whether FGFR1 overexpression contributes to PTX resistance and whether FGFR inhibition can enhance PTX efficacy in UC. The effects of PTX combined with the FGFR inhibitor BGJ398 were evaluated in UC cell lines by flow cytometry; Western blot analysis; cell viability, migration, and colony forming assays; and RNA interference. PTX+BGJ398 induced cell cycle arrest and apoptosis in UC cells with mesenchymal characteristics was accompanied by downregulation of cyclin D1 protein and upregulation of gamma-histone 2A family member X and cleaved poly(ADP-ribose) polymerase. Additionally, PTX+BGJ398 synergistically suppressed UC cell migration and colony formation via regulation of EMT-associated factors, while FGFR1 knockdown enhanced the antitumor effect of PTX. These findings provide a basis for development of effective strategies for overcoming PTX resistance in UC through inhibition of FGFR1 signaling.
Keyphrases
- cell cycle arrest
- cell death
- cell proliferation
- pi k akt
- cell migration
- epithelial mesenchymal transition
- signaling pathway
- flow cytometry
- stem cells
- induced apoptosis
- endoplasmic reticulum stress
- squamous cell carcinoma
- bone marrow
- south africa
- poor prognosis
- mass spectrometry
- long non coding rna
- gene expression
- high throughput
- single cell
- high resolution
- replacement therapy
- mesenchymal stem cells
- drug induced
- metastatic breast cancer