HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non–Small Cell Lung Cancer
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- Kimio Yonesaka
- 1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
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- Junko Tanizaki
- 1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
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- Osamu Maenishi
- 3Department of Pathology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
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- Koji Haratani
- 1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
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- Hisato Kawakami
- 1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
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- Kaoru Tanaka
- 1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
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- Hidetoshi Hayashi
- 1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
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- Kazuko Sakai
- 4Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
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- Yasutaka Chiba
- 5Clinical Research Center, Kindai University Hospital, Osaka-sayama, Osaka, Japan.
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- Asuka Tsuya
- 6Department of Medical Oncology, Izumi City General Hospital, Izumi, Osaka, Japan.
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- Hiroki Goto
- 7Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Edogawa, Tokyo, Japan.
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- Eri Otsuka
- 7Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Edogawa, Tokyo, Japan.
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- Hiroaki Okida
- 7Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Edogawa, Tokyo, Japan.
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- Maki Kobayashi
- 7Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Edogawa, Tokyo, Japan.
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- Ryoto Yoshimoto
- 7Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Edogawa, Tokyo, Japan.
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- Masanori Funabashi
- 7Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Edogawa, Tokyo, Japan.
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- Yuuri Hashimoto
- 8Oncology Research Laboratories I, Research Function, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa, Tokyo, Japan.
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- Kenji Hirotani
- 9Early Clinical Development Department, Development Function, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa, Tokyo, Japan.
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- Takashi Kagari
- 8Oncology Research Laboratories I, Research Function, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa, Tokyo, Japan.
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- Kazuto Nishio
- 4Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
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- Kazuhiko Nakagawa
- 1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, Japan.
Abstract
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non–small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody–drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.</jats:p> </jats:sec>
Journal
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- Clinical Cancer Research
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Clinical Cancer Research 28 (2), 390-403, 2021-12-17
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1360580237002698752
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- ISSN
- 15573265
- 10780432
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- Data Source
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- Crossref