癌症研究
表皮生长因子受体
肺癌
西妥昔单抗
PI3K/AKT/mTOR通路
医学
蛋白激酶B
癌症
表皮生长因子受体抑制剂
MAPK/ERK通路
信号转导
药理学
癌细胞
化学
酪氨酸激酶
作者
Kimio Yonesaka,Junko Tanizaki,Osamu Maenishi,Koji Haratani,Hisato Kawakami,Kaoru Tanaka,Hidetoshi Hayashi,Kazuko Sakai,Yasutaka Chiba,Asuka Tsuya,Hiroki Goto,Eri Otsuka,Hiroaki Okida,Maki Kobayashi,Ryoto Yoshimoto,Masanori Funabashi,Yuuri Hashimoto,Kenji Hirotani,Takashi Kagari,Kazuto Nishio,Kazuhiko Nakagawa
标识
DOI:10.1158/1078-0432.ccr-21-3359
摘要
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.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.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.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.
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