FGF2-FGFR1 pathway activation together with thymidylate synthase upregulation is induced in pemetrexed-resistant lung cancer cells.

FGF2-FGFR1 pathway activation together with thymidylate synthase upregulation is induced in pemetrexed-resistant lung cancer cells. Oncotarget. 2019 Feb 05;10(11):1171-1192 Authors: Miura K, Oba T, Hamanaka K, Ito KI Abstract Pemetrexed (MTA) is a folate antimetabolite used for treating non-small cell lung cancer. To elucidate the mechanisms of pemetrexed resistance in lung cancer, we established pemetrexed-resistant sublines in PC9 (mutant EGFR) and H1993 (wild-type EGFR) lung adenocarcinoma cell lines (PC9-MTA, H1993-MTA). Gene expression profile comparison by microarray analyses revealed enhanced fibroblast growth factor 2 (FGF2) and FGF receptor 1 (FGFR1) expression, confirmed by Western blotting, enzyme-linked immunosorbent assay, and reverse transcription-polymerase chain reaction. ERK phosphorylation was increased in PC9-MTA but decreased in H1993-MTA along with decreased downstream signaling molecule phosphorylation. Cellular morphological change from epithelial to spindle-shape together with increased mesenchymal marker protein expression was observed in H1993-MTA. SiRNA-mediated FGF2 knockdown partially restored pemetrexed sensitivity in both lines, whereas anti-FGFR1 inhibitor PD173074 restored pemetrexed sensitivity in PC9-MTA. FGF2 or FGFR1 inhibition decreased pERK levels in PC9-MTA but increased pEGFR levels together with downstream signaling molecule activation and reversed epithelial-mesenchymal transition marker pro...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research