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

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 es...

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Main Authors:	Azuma, Koichi, Kawahara, Akihiko, Sonoda, Kahori, Nakashima, Kazutaka, Tashiro, Kousuke, Watari, Kosuke, Izumi, Hiroto, Kage, Masayoshi, Kuwano, Michihiko, Ono, Mayumi, Hoshino, Tomoaki
Format:	Online
Language:	English
Published:	Impact Journals LLC 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171601/

id	pubmed-4171601
recordtype	oai_dc
spelling	pubmed-41716012014-09-23 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, Kousuke Watari, Kosuke Izumi, Hiroto Kage, Masayoshi Kuwano, Michihiko Ono, Mayumi Hoshino, Tomoaki Research Paper 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. Impact Journals LLC 2014-03-26 /pmc/articles/PMC4171601/ /pubmed/25115383 Text en Copyright: © 2014 Azuma et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Azuma, Koichi Kawahara, Akihiko Sonoda, Kahori Nakashima, Kazutaka Tashiro, Kousuke Watari, Kosuke Izumi, Hiroto Kage, Masayoshi Kuwano, Michihiko Ono, Mayumi Hoshino, Tomoaki
spellingShingle	Azuma, Koichi Kawahara, Akihiko Sonoda, Kahori Nakashima, Kazutaka Tashiro, Kousuke 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
author_facet	Azuma, Koichi Kawahara, Akihiko Sonoda, Kahori Nakashima, Kazutaka Tashiro, Kousuke Watari, Kosuke Izumi, Hiroto Kage, Masayoshi Kuwano, Michihiko Ono, Mayumi Hoshino, Tomoaki
author_sort	Azuma, Koichi
title	FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor
title_short	FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor
title_full	FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor
title_fullStr	FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor
title_full_unstemmed	FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor
title_sort	fgfr1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-egfr family kinase inhibitor
description	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.
publisher	Impact Journals LLC
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171601/
_version_	1613136113926406144

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

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