FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor
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Koichi Azuma1, Akihiko Kawahara2, Kahori Sonoda3, Kazutaka Nakashima2 ,Kousuke Tashiro4, Kosuke Watari3, Hiroto Izumi5, Masayoshi Kage2, Michihiko Kuwano6, Mayumi Ono3and Tomoaki Hoshino1
1 Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
2 Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka, Japan
3 Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
4 Department of Bioscience and Biotechnology, Kyushu University, Fukuoka, Japan
5 Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan
6 Laboratory of Molecular Cancer Biology, Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
Koichi Azuma, email:
Keywords: activating EGFR mutation, FGFR1, non-small cell lung cancer, afatinib
Received: January 31, 2014 Accepted: March 24, 2014 Published: March 26, 2014
Most NSCLC patients with EGFR mutations benefit from treatment with EGFR-TKIs, but the clinical efficacy of EGFR-TKIs is limited by the appearance of drug resistance. Multiple kinase inhibitors of EGFR family proteins such as afatinib have been newly developed to overcome such drug resistance. We established afatinib-resistant cell lines after chronic exposure of activating EGFR mutation-positive PC9 cells to afatinib. Afatinib-resistant cells showed following specific characteristics as compared to PC9:  Expression of EGFR family proteins and their phosphorylated molecules was markedly downregulated by selection of afatinib resistance;  Expression of FGFR1 and its ligand FGF2 was alternatively upregulated;  Treatment with anti-FGF2 neutralizing antibody blocked enhanced phosphorylation of FGFR in resistant clone;  Both resistant clones showed collateral sensitivity to PD173074, a small-molecule FGFR-TKIs, and treatment with either PD173074 or FGFR siRNA exacerbated suppression of both afatinib-resistant Akt and Erk phosphorylation when combined with afatinib;  Expression of twist was markedly augmented in resistant sublines, and twist knockdown specifically suppressed FGFR expression and cell survival. Together, enhanced expression of FGFR1 and FGF2 thus plays as an escape mechanism for cell survival of afatinib-resistant cancer cells, that may compensate the loss of EGFR-driven signaling pathway.
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