ID | 66932 |
フルテキストURL | |
著者 |
Hara, Naofumi
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Ichihara, Eiki
Department of Allergy and Respiratory Medicine, Okayama University Hospital
Kaken ID
publons
Kano, Hirohisa
Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital
Ando, Chihiro
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Morita, Ayako
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Nishi, Tatsuya
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Okawa, Sachi
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Nakasuka, Takamasa
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Hirabae, Atsuko
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Abe, Masaya
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Asada, Noboru
Department of Hematology and Oncology, Okayama University Hospital
Kaken ID
researchmap
Ninomiya, Kiichiro
Center for Comprehensive Genomic Medicine, Okayama University Hospital
Kaken ID
Makimoto, Go
Center for Clinical Oncology, Okayama University Hospital
Fujii, Masanori
Department of Allergy and Respiratory Medicine, Okayama University Hospital
Kubo, Toshio
Department of Allergy and Respiratory Medicine, Okayama University Hospital
Kaken ID
researchmap
Ohashi, Kadoaki
Department of Allergy and Respiratory Medicine, Okayama University Hospital
ORCID
Kaken ID
researchmap
Hotta, Katsuyuki
Center for Innovative Clinical Medicine, Okayama University Hospital
Kaken ID
publons
researchmap
Maeda, Yoshinobu
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Kaken ID
researchmap
Kiura, Katsuyuki
Department of Allergy and Respiratory Medicine, Okayama University Hospital
ORCID
Kaken ID
publons
researchmap
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抄録 | Background: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance.
Methods: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC. Results: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation. Conclusions: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC. |
キーワード | Epidermal growth factor receptor (EGFR)
non-small cell lung cancer (NSCLC)
cell cycle
CDK4/6 inhibitor
|
発行日 | 2023-10-31
|
出版物タイトル |
Translational Lung Cancer Research
|
巻 | 12巻
|
号 | 10号
|
出版者 | AME Publishing Company
|
ISSN | 2218-6751
|
資料タイプ |
学術雑誌論文
|
言語 |
英語
|
OAI-PMH Set |
岡山大学
|
著作権者 | © Translational Lung Cancer Research.
|
論文のバージョン | publisher
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PubMed ID | |
DOI | |
Web of Science KeyUT | |
関連URL | isVersionOf https://doi.org/10.21037/tlcr-23-99
|
Citation | https://creativecommons.org/licenses/by-nc-nd/4.0/
|
助成機関名 |
Japan Society for the Promotion of Science
Japan Lung Cancer Society
|
助成番号 | 21K08179
|