title: Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.
abstract: Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a common feature in lung cancer (LC). In this study, we evaluated the antitumor activity of and the mechanisms underlying acquired resistance to two potent selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5 with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581 and DMS114, were sensitive to FGFR inhibitors (IC50<250 nm). Clones of FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK) array and immunoblotting analyses showed strong overexpression and activation of Met in H1581AR/BR cells, compared with that in the parental cells. Gene set enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that cytokine-cytokine receptor interaction pathways were significantly enriched in H1581AR/BR cells, with Met contributing significantly to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ hybridization analyses showed MET amplification in H1581AR, but not in H1581BR, cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short interfering RNA (siRNA) synergistically inhibited cell proliferation in both H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR inhibitors not only altered cellular morphology, but also promoted migration and invasion of resistant clones, in part by inducing epithelial-to-mesenchymal transition. Taken together, our data suggest that Met activation is sufficient to bypass dependency on FGFR signaling. Concurrent inhibition of the Met and FGFR pathways may have synergistic clinical benefits when targeting FGFR-dependent LC.
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: S-M
authors.initials: SM
authors.lastname: Kim
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: M R
authors.initials: MR
authors.lastname: Yun
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: H N
authors.initials: HN
authors.lastname: Kang
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: K-H
authors.initials: KH
authors.lastname: Pyo
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Park
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: J M
authors.initials: JM
authors.lastname: Lee
authors.affiliation: JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
authors.forename: H M
authors.initials: HM
authors.lastname: Choi
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Ellinghaus
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ocker
authors.affiliation: Division of Pathology NSABP, Pittsburgh, PA, USA.|Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: S
authors.initials: S
authors.lastname: Paik
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: H R
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: B C
authors.initials: BC
authors.lastname: Cho