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FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor.

Oncotarget (2014-08-15)
Koichi Azuma, Akihiko Kawahara, Kahori Sonoda, Kazutaka Nakashima, Kousuke Tashiro, Kosuke Watari, Hiroto Izumi, Masayoshi Kage, Michihiko Kuwano, Mayumi Ono, Tomoaki Hoshino
ABSTRACT

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: [1] Expression of EGFR family proteins and their phosphorylated molecules was markedly downregulated by selection of afatinib resistance; [2] Expression of FGFR1 and its ligand FGF2 was alternatively upregulated; [3] Treatment with anti-FGF2 neutralizing antibody blocked enhanced phosphorylation of FGFR in resistant clone; [4] 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; [5] 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
cis-Diammineplatinum(II) dichloride, crystalline
Cisplatin, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
cis-Diamineplatinum(II) dichloride, ≥99.9% trace metals basis
Sigma-Aldrich
trans-Platinum(II)diammine dichloride
Cisplatin impurity A, European Pharmacopoeia (EP) Reference Standard
USP
Transplatin, United States Pharmacopeia (USP) Reference Standard