Cargando…

Preclinical assessment of combination therapy of EGFR tyrosine kinase inhibitors in a highly heterogeneous tumor model

The development of tyrosine kinase inhibitors (TKIs) has improved the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The current research priority is to provide viable treatments for patients who have drug-resistant EGFR mutations. We evaluate...

Descripción completa

Detalles Bibliográficos
Autores principales: Ikeuchi, Hiroshi, Hirose, Takeshi, Ikegami, Masachika, Takamochi, Kazuya, Suzuki, Kenji, Mano, Hiroyuki, Kohsaka, Shinji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033582/
https://www.ncbi.nlm.nih.gov/pubmed/35304574
http://dx.doi.org/10.1038/s41388-022-02263-4
_version_ 1784692925187227648
author Ikeuchi, Hiroshi
Hirose, Takeshi
Ikegami, Masachika
Takamochi, Kazuya
Suzuki, Kenji
Mano, Hiroyuki
Kohsaka, Shinji
author_facet Ikeuchi, Hiroshi
Hirose, Takeshi
Ikegami, Masachika
Takamochi, Kazuya
Suzuki, Kenji
Mano, Hiroyuki
Kohsaka, Shinji
author_sort Ikeuchi, Hiroshi
collection PubMed
description The development of tyrosine kinase inhibitors (TKIs) has improved the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The current research priority is to provide viable treatments for patients who have drug-resistant EGFR mutations. We evaluated the drug sensitivity of various EGFR mutants to monotherapies and combination therapies of EGFR-TKIs. In vitro, the transforming potential and drug sensitivity of 357 EGFR variants were assessed. In vivo, we tested the sensitivity of EGFR variants to different regimens of EGFR-TKIs by examining changes in the proportion of each variant within the tumor. Out of 357 variants thoroughly examined for transforming activities, 144 (40.3%) and 282 (79.0%) transformed 3T3 and Ba/F3 cells, respectively. Among the latter variants, 50 (17.7%) were found to be resistant or only partly resistant to osimertinib or afatinib. Four of 25 afatinib-resistant variants (16%) were sensitive to osimertinib, whereas 25 of 46 osimertinib-resistant variants (54.3%) were sensitive to afatinib. Despite the lack of a synergistic impact, TKI combination treatment effectively reduced in vivo the heterogeneous tumors composed of 3T3 cells with different EGFR variants. Regimens starting with afatinib and subsequently switched to osimertinib suppressed tumor development more efficiently than the opposite combination. Combination EGFR-TKI treatment may decrease tumor growth and prevent the development of resistant variants. This work created an experimental model of a heterogeneous tumor to find the best combination therapy regimen and proposes a basic notion of EGFR-TKI combination therapy to enhance the prognosis of NSCLC patients.
format Online
Article
Text
id pubmed-9033582
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-90335822022-04-29 Preclinical assessment of combination therapy of EGFR tyrosine kinase inhibitors in a highly heterogeneous tumor model Ikeuchi, Hiroshi Hirose, Takeshi Ikegami, Masachika Takamochi, Kazuya Suzuki, Kenji Mano, Hiroyuki Kohsaka, Shinji Oncogene Article The development of tyrosine kinase inhibitors (TKIs) has improved the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The current research priority is to provide viable treatments for patients who have drug-resistant EGFR mutations. We evaluated the drug sensitivity of various EGFR mutants to monotherapies and combination therapies of EGFR-TKIs. In vitro, the transforming potential and drug sensitivity of 357 EGFR variants were assessed. In vivo, we tested the sensitivity of EGFR variants to different regimens of EGFR-TKIs by examining changes in the proportion of each variant within the tumor. Out of 357 variants thoroughly examined for transforming activities, 144 (40.3%) and 282 (79.0%) transformed 3T3 and Ba/F3 cells, respectively. Among the latter variants, 50 (17.7%) were found to be resistant or only partly resistant to osimertinib or afatinib. Four of 25 afatinib-resistant variants (16%) were sensitive to osimertinib, whereas 25 of 46 osimertinib-resistant variants (54.3%) were sensitive to afatinib. Despite the lack of a synergistic impact, TKI combination treatment effectively reduced in vivo the heterogeneous tumors composed of 3T3 cells with different EGFR variants. Regimens starting with afatinib and subsequently switched to osimertinib suppressed tumor development more efficiently than the opposite combination. Combination EGFR-TKI treatment may decrease tumor growth and prevent the development of resistant variants. This work created an experimental model of a heterogeneous tumor to find the best combination therapy regimen and proposes a basic notion of EGFR-TKI combination therapy to enhance the prognosis of NSCLC patients. Nature Publishing Group UK 2022-03-19 2022 /pmc/articles/PMC9033582/ /pubmed/35304574 http://dx.doi.org/10.1038/s41388-022-02263-4 Text en © The Author(s) 2022 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
Ikeuchi, Hiroshi
Hirose, Takeshi
Ikegami, Masachika
Takamochi, Kazuya
Suzuki, Kenji
Mano, Hiroyuki
Kohsaka, Shinji
Preclinical assessment of combination therapy of EGFR tyrosine kinase inhibitors in a highly heterogeneous tumor model
title Preclinical assessment of combination therapy of EGFR tyrosine kinase inhibitors in a highly heterogeneous tumor model
title_full Preclinical assessment of combination therapy of EGFR tyrosine kinase inhibitors in a highly heterogeneous tumor model
title_fullStr Preclinical assessment of combination therapy of EGFR tyrosine kinase inhibitors in a highly heterogeneous tumor model
title_full_unstemmed Preclinical assessment of combination therapy of EGFR tyrosine kinase inhibitors in a highly heterogeneous tumor model
title_short Preclinical assessment of combination therapy of EGFR tyrosine kinase inhibitors in a highly heterogeneous tumor model
title_sort preclinical assessment of combination therapy of egfr tyrosine kinase inhibitors in a highly heterogeneous tumor model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033582/
https://www.ncbi.nlm.nih.gov/pubmed/35304574
http://dx.doi.org/10.1038/s41388-022-02263-4
work_keys_str_mv AT ikeuchihiroshi preclinicalassessmentofcombinationtherapyofegfrtyrosinekinaseinhibitorsinahighlyheterogeneoustumormodel
AT hirosetakeshi preclinicalassessmentofcombinationtherapyofegfrtyrosinekinaseinhibitorsinahighlyheterogeneoustumormodel
AT ikegamimasachika preclinicalassessmentofcombinationtherapyofegfrtyrosinekinaseinhibitorsinahighlyheterogeneoustumormodel
AT takamochikazuya preclinicalassessmentofcombinationtherapyofegfrtyrosinekinaseinhibitorsinahighlyheterogeneoustumormodel
AT suzukikenji preclinicalassessmentofcombinationtherapyofegfrtyrosinekinaseinhibitorsinahighlyheterogeneoustumormodel
AT manohiroyuki preclinicalassessmentofcombinationtherapyofegfrtyrosinekinaseinhibitorsinahighlyheterogeneoustumormodel
AT kohsakashinji preclinicalassessmentofcombinationtherapyofegfrtyrosinekinaseinhibitorsinahighlyheterogeneoustumormodel