Reference Detail

Ref Type Journal Article
PMID (27429073)
Authors Kim SM, Kim H, Yun MR, Kang HN, Pyo KH, Park HJ, Lee JM, Choi HM, Ellinghaus P, Ocker M, Paik S, Kim HR, Cho BC
Title Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy.
Journal Oncogenesis
Vol 5
Issue 7
Date 2016 Jul 18
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Rogaratinib Rogaratinib 9 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
Rogaratinib BAY 1163877|BAY-1163877|BAY1163877 FGFR Inhibitor (Pan) 18 Rogaratinib (BAY 1163877) is a small molecule pan-FGFR inhibitor, which reduces downstream signaling, potentially resulting in decreased tumor cell proliferation (PMID: 27429073, PMID: 29451369).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 amp MET over exp lung cancer resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, MET overexpression and activation was identified as the mechanism mediating acquired Rogaratinib (BAY 1163877) resistance in a FGFR1 amplified lung cancer cell line in culture (PMID: 27429073). 27429073
FGFR1 amp MET amp lung cancer sensitive AZD4547 + Crizotinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 and Xalkori (crizotinib) synergistically inhibited proliferation of FGFR1 amplified lung cancer cells that acquired resistance to AZD4547 through MET amplification in culture (PMID: 27429073). 27429073
FGFR1 amp MET pos lung cancer resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, FGFR1-amplified lung cancer cell lines with Met expression were resistant to AZD4547 in culture (PMID: 27429073). 27429073
FGFR1 amp MET amp lung cancer resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, MET amplification was identified as the mechanism mediating acquired AZD4547 resistance in a FGFR1 amplified lung cancer cell line in culture (PMID: 27429073). 27429073
FGFR1 amp MET over exp lung cancer sensitive Crizotinib + Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Rogaratinib (BAY 1163877) and Xalkori (crizotinib) synergistically inhibited proliferation of FGFR1 amplified lung cancer cells that acquired resistance to Rogaratinib (BAY 1163877) through MET overexpression and activation in culture (PMID: 27429073). 27429073
FGFR1 amp MET dec exp lung cancer sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited Erk signaling and proliferation of FGFR1-amplified lung cancer cell lines with undetectable Met expression in culture (PMID: 27429073). 27429073
FGFR1 amp MET pos lung cancer resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, FGFR1-amplified lung cancer cell lines with Met expression were resistant to Rogaratinib (BAY 1163877) in culture (PMID: 27429073). 27429073
FGFR1 amp MET dec exp lung cancer sensitive Rogaratinib Preclinical - Cell culture Actionable In a preclinical study, Rogaratinib (BAY 1163877) inhibited Erk signaling and proliferation of FGFR1-amplified lung cancer cell lines with undetectable Met expression in culture (PMID: 27429073). 27429073