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

Koichi Azuma, Akihiko Kawahara, Kahori Sonoda, Kazutaka Nakashima, Kosuke Tashiro, Kosuke Watari, Hiroto Izumi, Masayoshi Kage, Michihiko Kuwano, Mayumi Ono, Tomoaki Hoshino

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Most NSCLC patients with EGFR mutations benefit from treatment with EGFRTKIs,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 afatinibresistant 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.

Original languageEnglish
Pages (from-to)5908-5919
Number of pages12
JournalOncotarget
Volume5
Issue number15
DOIs
Publication statusPublished - Jan 1 2014

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Lung Neoplasms
Phosphotransferases
Fibroblast Growth Factor 2
Drug Resistance
Cell Survival
Clone Cells
Phosphorylation
Mutation
BIBW 2992
Neutralizing Antibodies
Small Interfering RNA
Proteins
Therapeutics
Down-Regulation
Ligands
Cell Line
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor. / Azuma, Koichi; Kawahara, Akihiko; Sonoda, Kahori; Nakashima, Kazutaka; Tashiro, Kosuke; Watari, Kosuke; Izumi, Hiroto; Kage, Masayoshi; Kuwano, Michihiko; Ono, Mayumi; Hoshino, Tomoaki.

In: Oncotarget, Vol. 5, No. 15, 01.01.2014, p. 5908-5919.

Research output: Contribution to journalArticle

Azuma, K, Kawahara, A, Sonoda, K, Nakashima, K, Tashiro, K, Watari, K, Izumi, H, Kage, M, Kuwano, M, Ono, M & Hoshino, T 2014, 'FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor' Oncotarget, vol. 5, no. 15, pp. 5908-5919. https://doi.org/10.18632/oncotarget.1866
Azuma, Koichi ; Kawahara, Akihiko ; Sonoda, Kahori ; Nakashima, Kazutaka ; Tashiro, Kosuke ; Watari, Kosuke ; Izumi, Hiroto ; Kage, Masayoshi ; Kuwano, Michihiko ; Ono, Mayumi ; Hoshino, Tomoaki. / FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor. In: Oncotarget. 2014 ; Vol. 5, No. 15. pp. 5908-5919.
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