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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Vydáno v:	The Journal of thoracic and cardiovascular surgery Ročník 162; číslo 2; s. 463
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.08.2021
Témata:	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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Abstract	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.
AbstractList	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.OBJECTIVEInnate 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.METHODSNon-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.RESULTSNon-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.CONCLUSIONSNeuropilin-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. 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.
Author	Nasarre, Cecile Drabkin, Harry A Gibney, Barry C Pagano, Rose Peterson, Yuri K Nasarre, Patrick Gooz, Monika Denlinger, Chadrick E Dimou, Anastasios Armeson, Kent E Gemmill, Robert M
Author_xml	– sequence: 1 givenname: Anastasios surname: Dimou fullname: Dimou, Anastasios organization: Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC – sequence: 2 givenname: Cecile surname: Nasarre fullname: Nasarre, Cecile organization: Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC – sequence: 3 givenname: Yuri K surname: Peterson fullname: Peterson, Yuri K organization: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC – sequence: 4 givenname: Rose surname: Pagano fullname: Pagano, Rose organization: Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC – sequence: 5 givenname: Monika surname: Gooz fullname: Gooz, Monika organization: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC – sequence: 6 givenname: Patrick surname: Nasarre fullname: Nasarre, Patrick organization: Department of Surgery, Medical University of South Carolina, Charleston, SC – sequence: 7 givenname: Harry A surname: Drabkin fullname: Drabkin, Harry A organization: Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC – sequence: 8 givenname: Kent E surname: Armeson fullname: Armeson, Kent E organization: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC – sequence: 9 givenname: Barry C surname: Gibney fullname: Gibney, Barry C organization: Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC – sequence: 10 givenname: Robert M surname: Gemmill fullname: Gemmill, Robert M organization: Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC – sequence: 11 givenname: Chadrick E surname: Denlinger fullname: Denlinger, Chadrick E email: denlinge@musc.edu organization: Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC. Electronic address: denlinge@musc.edu
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SubjectTerms	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
Title	Neuropilin-2b facilitates resistance to tyrosine kinase inhibitors in non-small cell lung cancer
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