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Ref Type Journal Article
PMID (30257990)
Authors Ryan MR, Sohl CD, Luo B, Anderson KS
Title The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT.
Journal Molecular cancer research : MCR
Vol 17
Issue 2
Date 2019 02
URL
Abstract Text FGFR1 has been implicated in numerous cancer types including squamous cell lung cancer, a subset of non-small cell lung cancer with a dismal 5-year survival rate. Small-molecule inhibitors targeting FGFR1 are currently in clinical trials, with AZD4547 being one of the furthest along; however, the development of drug resistance is a major challenge for targeted therapies. A prevalent mechanism of drug resistance in kinases occurs through mutation of the gatekeeper residue, V561M in FGFR1; however, mechanisms underlying V561M resistance to AZD4547 are not fully understood. Here, the cellular consequences of the V561M gatekeeper mutation were characterized, and it was found that although AZD4547 maintains nanomolar affinity for V561M FGFR1, based on in vitro binding assays, cells expressing V561M demonstrate dramatic resistance to AZD4547 driven by increased STAT3 activation downstream of V561M FGFR1. The data reveal that the V561M mutation biases cells toward a more mesenchymal phenotype, including increased levels of proliferation, migration, invasion, and anchorage-independent growth, which was confirmed using CyTOF, a novel single-cell analysis tool. Using shRNA knockdown, loss of STAT3 restored sensitivity of cancer cells expressing V561M FGFR1 to AZD4547. Thus, the data demonstrate that combination therapies including FGFR and STAT3 may overcome V561M FGFR1-driven drug resistance in the clinic. IMPLICATIONS: The V561M FGFR1 gatekeeper mutation leads to devastating drug resistance through activation of STAT3 and the epithelial-mesenchymal transition; this study demonstrates that FGFR1 inhibitor sensitivity can be restored upon STAT3 knockdown.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR1 V561M missense gain of function FGFR1 V561M lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). V561M results in increased Fgfr1 autophosphorylation and has been shown to be associated with resistance to tyrosine kinase inhibitors (PMID: 25686244, PMID: 15157880, PMID: 28646488), and leads to increased Stat3 phosphorylation and STAT3-dependent gene expression, elevated expression of mesenchymal genes, and increased cell proliferation, migration, and anchorage-independent growth in culture (PMID: 30257990). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 V561M lung non-small cell carcinoma resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cells expressing FGFR1 V561M demonstrated resistance to AZD4547 in culture (PMID: 30257990). 30257990