Neuropilin-2b facilitates resistance to tyrosine kinase inhibitors in non-small cell lung cancer

Innate and acquired resistance is the principle factor limiting the efficacy of tyrosine kinase inhibitors in lung cancer. We have observed a dramatic upregulation of the cell surface co-receptor neuropilin-2b in lung cancers clinically treated with tyrosine kinase inhibitors correlating with acquir...

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Veröffentlicht in:The Journal of thoracic and cardiovascular surgery Jg. 162; H. 2; S. 463
Hauptverfasser: Dimou, Anastasios, Nasarre, Cecile, Peterson, Yuri K, Pagano, Rose, Gooz, Monika, Nasarre, Patrick, Drabkin, Harry A, Armeson, Kent E, Gibney, Barry C, Gemmill, Robert M, Denlinger, Chadrick E
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.08.2021
Schlagworte:
A549 Cells
Acrylamides - pharmacology
Aniline Compounds - pharmacology
Antineoplastic Agents - pharmacology
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - enzymology
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Cell Movement - drug effects
Cell Proliferation - drug effects
Drug Resistance, Neoplasm
Enzyme Activation
Gefitinib - pharmacology
Glycogen Synthase Kinase 3 beta - metabolism
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - enzymology
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Neoplasm Invasiveness
Neuropilin-2 - genetics
Neuropilin-2 - metabolism
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Proteolysis
Proto-Oncogene Proteins c-akt - metabolism
PTEN Phosphohydrolase - metabolism
lung cancer
migration
tyrosine kinase inhibitor
resistance
survival
ISSN:1097-685X, 1097-685X
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Zusammenfassung:Innate and acquired resistance is the principle factor limiting the efficacy of tyrosine kinase inhibitors in lung cancer. We have observed a dramatic upregulation of the cell surface co-receptor neuropilin-2b in lung cancers clinically treated with tyrosine kinase inhibitors correlating with acquired resistance. We hypothesize that neuropilin-2b plays a functional role in acquired tyrosine kinase inhibitor resistance. Non-small cell lung cancer proliferation and survival were determined during chronic tyrosine kinase inhibitor exposure in the presence or absence of neuropilin-2b knock-down. Interactions of neuropilin-2a and neuropilin-2b isoforms with PTEN and GSK3β were assessed by immunoprecipitation. Neuropilin-2a and neuropilin-2b mutants deleted for their cytoplasmic domains were used to identify regions responsible for neuropilin-2b-GSK3β interaction. Because GSK3β is known to phosphorylate and degrade PTEN, phospho-PTEN and total PTEN levels were assessed after transfection of neuropilin-2a and neuropilin-2b wild-type and mutant constructs. Non-small cell lung cancer cells chronically treated with gefitinib or osimertinib developed drug resistance and exhibited logarithmic growth in the presence of endothelial growth factor receptor tyrosine kinase inhibitors. However, neuropilin-2b knockdown cells remained sensitive to gefitinib. Likewise, neuropilin-2b knockdown suppressed and neuropilin-2a knockdown enhanced cellular migration. Acquired drug resistance and cell migration correlated with neuropilin-2b-dependent AKT activation with the intermediate step of GSK3β-dependent PTEN degradation. A specific binding site for GSK3β on the cytoplasmic domain of neuropilin-2b was identified with truncated protein constructs and computer modeling. Neuropilin-2b facilitates non-small cell lung cancer resistance to tyrosine kinase inhibitors, and this biological effect relates to AKT activation. Neuropilin-2b GSK3β interactions appear to be essential for PTEN degradation and AKT activation in lung cancer cells. Disruption of the neuropilin-2b GSK3β interaction may represent a novel treatment strategy to preserve sensitivity to tyrosine kinase inhibitors in non-small cell lung cancer.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1097-685X
1097-685X
DOI:10.1016/j.jtcvs.2020.03.166