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Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line
In non-small cell lung cancer (NSCLC), oncogenic driver mutations including those in KRAS and EGFR are typically mutually exclusive. However, recent reports indicate that multiple driver mutations are found in a certain percentage of cancers, and that the therapeutic responses of such cases with co-...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055889/ https://www.ncbi.nlm.nih.gov/pubmed/32130260 http://dx.doi.org/10.1371/journal.pone.0229712 |
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author | Tsukumo, Yoshinori Naito, Mikihiko Suzuki, Takayoshi |
author_facet | Tsukumo, Yoshinori Naito, Mikihiko Suzuki, Takayoshi |
author_sort | Tsukumo, Yoshinori |
collection | PubMed |
description | In non-small cell lung cancer (NSCLC), oncogenic driver mutations including those in KRAS and EGFR are typically mutually exclusive. However, recent reports indicate that multiple driver mutations are found in a certain percentage of cancers, and that the therapeutic responses of such cases with co-mutations of driver genes are largely unclear. Here, using CRISPR-Cas9-mediated genome editing, we generated isogenic cell lines harboring one or two copies of an EGFR-activating mutation from the human NSCLC cell line A549, which is known to harbor a homozygous KRAS gene mutation. In comparison with parent cells with KRAS mutation alone, cells with concomitant EGFR mutation exhibited higher sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) but not to conventional anti-cancer drugs. In particular, cells with two copies of EGFR mutation were markedly more sensitive to EGFR-TKIs compared with parent cells. Thus, the presence of concomitant EGFR mutation can affect the TKI response of KRAS-mutated cells, implying that EGFR-TKI may represent an effective treatment option against NSCLC with EGFR/KRAS co-mutation. |
format | Online Article Text |
id | pubmed-7055889 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-70558892020-03-13 Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line Tsukumo, Yoshinori Naito, Mikihiko Suzuki, Takayoshi PLoS One Research Article In non-small cell lung cancer (NSCLC), oncogenic driver mutations including those in KRAS and EGFR are typically mutually exclusive. However, recent reports indicate that multiple driver mutations are found in a certain percentage of cancers, and that the therapeutic responses of such cases with co-mutations of driver genes are largely unclear. Here, using CRISPR-Cas9-mediated genome editing, we generated isogenic cell lines harboring one or two copies of an EGFR-activating mutation from the human NSCLC cell line A549, which is known to harbor a homozygous KRAS gene mutation. In comparison with parent cells with KRAS mutation alone, cells with concomitant EGFR mutation exhibited higher sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) but not to conventional anti-cancer drugs. In particular, cells with two copies of EGFR mutation were markedly more sensitive to EGFR-TKIs compared with parent cells. Thus, the presence of concomitant EGFR mutation can affect the TKI response of KRAS-mutated cells, implying that EGFR-TKI may represent an effective treatment option against NSCLC with EGFR/KRAS co-mutation. Public Library of Science 2020-03-04 /pmc/articles/PMC7055889/ /pubmed/32130260 http://dx.doi.org/10.1371/journal.pone.0229712 Text en © 2020 Tsukumo et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Tsukumo, Yoshinori Naito, Mikihiko Suzuki, Takayoshi Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line |
title | Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line |
title_full | Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line |
title_fullStr | Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line |
title_full_unstemmed | Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line |
title_short | Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line |
title_sort | influence of egfr-activating mutations on sensitivity to tyrosine kinase inhibitors in a kras mutant non-small cell lung cancer cell line |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055889/ https://www.ncbi.nlm.nih.gov/pubmed/32130260 http://dx.doi.org/10.1371/journal.pone.0229712 |
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