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A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer

Tyrosine kinase inhibitors (TKIs) targeting EGFR-mutant lung cancers promote a range of tumor regression responses to yield variable residual disease, a likely incubator for acquired resistance. Herein, rapid transcriptional responses induced by TKIs early in treatment that associate with the range...

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Autores principales: Gurule, Natalia J., McCoach, Caroline E., Hinz, Trista K., Merrick, Daniel T., Van Bokhoven, Adriaan, Kim, Jihye, Patil, Tejas, Calhoun, Jacob, Nemenoff, Raphael A., Tan, Aik Choon, Doebele, Robert C., Heasley, Lynn E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129124/
https://www.ncbi.nlm.nih.gov/pubmed/34001994
http://dx.doi.org/10.1038/s41698-021-00181-4
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author Gurule, Natalia J.
McCoach, Caroline E.
Hinz, Trista K.
Merrick, Daniel T.
Van Bokhoven, Adriaan
Kim, Jihye
Patil, Tejas
Calhoun, Jacob
Nemenoff, Raphael A.
Tan, Aik Choon
Doebele, Robert C.
Heasley, Lynn E.
author_facet Gurule, Natalia J.
McCoach, Caroline E.
Hinz, Trista K.
Merrick, Daniel T.
Van Bokhoven, Adriaan
Kim, Jihye
Patil, Tejas
Calhoun, Jacob
Nemenoff, Raphael A.
Tan, Aik Choon
Doebele, Robert C.
Heasley, Lynn E.
author_sort Gurule, Natalia J.
collection PubMed
description Tyrosine kinase inhibitors (TKIs) targeting EGFR-mutant lung cancers promote a range of tumor regression responses to yield variable residual disease, a likely incubator for acquired resistance. Herein, rapid transcriptional responses induced by TKIs early in treatment that associate with the range of patient responses were explored. RNAseq was performed on EGFR mutant cell lines treated in vitro with osimertinib and on tumor biopsies of eight EGFR mutant lung cancer patients before and after 2 weeks of TKI treatment. Data were evaluated for gene expression programs altered upon TKI treatment. Chemokine and cytokine expression were measured by ELISA and quantitative RT-PCR. IκB Kinase (IKK) and JAK-STAT pathway dependence was tested with pharmacologic and molecular inhibitors. Tumor sections were stained for the T-cell marker CD3. Osimertinib stimulated dynamic, yet wide-ranging interferon (IFN) program regulation in EGFR mutant cell lines. IL6 and CXCL10 induction varied markedly among the EGFR mutant cell lines and was sensitive to IKK and JAK-STAT inhibitors. Analysis of matched patient biopsy pairs revealed marked, yet varied enrichment of IFN transcriptional programs, effector immune cell signatures and T-cell content in treated tumors that positively correlated with time to progression in the patients. EGFR-specific TKIs induce wide-ranging IFN response program activation originating within the cancer cell. The strong association of IFN program induction and duration of clinical response indicates that the TKI-induced IFN program instructs variable recruitment and participation of immune cells in the overall therapeutic response.
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spelling pubmed-81291242021-05-27 A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer Gurule, Natalia J. McCoach, Caroline E. Hinz, Trista K. Merrick, Daniel T. Van Bokhoven, Adriaan Kim, Jihye Patil, Tejas Calhoun, Jacob Nemenoff, Raphael A. Tan, Aik Choon Doebele, Robert C. Heasley, Lynn E. NPJ Precis Oncol Article Tyrosine kinase inhibitors (TKIs) targeting EGFR-mutant lung cancers promote a range of tumor regression responses to yield variable residual disease, a likely incubator for acquired resistance. Herein, rapid transcriptional responses induced by TKIs early in treatment that associate with the range of patient responses were explored. RNAseq was performed on EGFR mutant cell lines treated in vitro with osimertinib and on tumor biopsies of eight EGFR mutant lung cancer patients before and after 2 weeks of TKI treatment. Data were evaluated for gene expression programs altered upon TKI treatment. Chemokine and cytokine expression were measured by ELISA and quantitative RT-PCR. IκB Kinase (IKK) and JAK-STAT pathway dependence was tested with pharmacologic and molecular inhibitors. Tumor sections were stained for the T-cell marker CD3. Osimertinib stimulated dynamic, yet wide-ranging interferon (IFN) program regulation in EGFR mutant cell lines. IL6 and CXCL10 induction varied markedly among the EGFR mutant cell lines and was sensitive to IKK and JAK-STAT inhibitors. Analysis of matched patient biopsy pairs revealed marked, yet varied enrichment of IFN transcriptional programs, effector immune cell signatures and T-cell content in treated tumors that positively correlated with time to progression in the patients. EGFR-specific TKIs induce wide-ranging IFN response program activation originating within the cancer cell. The strong association of IFN program induction and duration of clinical response indicates that the TKI-induced IFN program instructs variable recruitment and participation of immune cells in the overall therapeutic response. Nature Publishing Group UK 2021-05-17 /pmc/articles/PMC8129124/ /pubmed/34001994 http://dx.doi.org/10.1038/s41698-021-00181-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Gurule, Natalia J.
McCoach, Caroline E.
Hinz, Trista K.
Merrick, Daniel T.
Van Bokhoven, Adriaan
Kim, Jihye
Patil, Tejas
Calhoun, Jacob
Nemenoff, Raphael A.
Tan, Aik Choon
Doebele, Robert C.
Heasley, Lynn E.
A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer
title A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer
title_full A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer
title_fullStr A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer
title_full_unstemmed A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer
title_short A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer
title_sort tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in egfr-mutant lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129124/
https://www.ncbi.nlm.nih.gov/pubmed/34001994
http://dx.doi.org/10.1038/s41698-021-00181-4
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