PO.MCB03.02 · 分子与细胞生物学

HER2过表达导致EGFR突变型肺癌对osimertinib耐药

HER2 overexpression confers osimertinib resistance in EGFR-mutant lung cancer

编号 3297 展板 4 时间 4/20 02:00–05:00 区域 Section 24 主讲 Gaku Yamamoto, MD;PhD

分会场 RTK-ERBB-PI3K and New Targets in Therapeutic Resistance

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作者与单位 Authors & Affiliations

Gaku Yamamoto, Yu Tanaka, Miku Tsukuda, Sato Sayaka, Saori Matsui, Tetsuya Sakai, Hiroki Izumi, Eri Sugiyama, Yoshitaka Zenke, Shigeki Umemura, Kiyotaka Yoh, Koichi Goto, Hibiki Udagawa

National Cancer Center Hospital East, Kashiwa, Japan

摘要 Abstract

中文摘要

HER2扩增见于2-5%对osimertinib获得性耐药的EGFR突变型肺癌患者中；然而，其介导耐药的确切机制尚不清楚。本研究旨在通过多种临床前方法阐明HER2异常如何促成对osimertinib的获得性耐药。利用PC9（EGFR外显子19缺失）和H1975（EGFR L858R）细胞株，通过慢病毒转导构建了稳定过表达HER2的EGFR突变型细胞株。尽管HER2过表达细胞在体外对osimertinib的短期（3天）敏感性与空载体对照相当，但长期实验（>7天）显示，两种HER2过表达模型中耐药克隆形成均显著增加。随后，在裸鼠中建立了携带HER2过表达细胞的异种移植模型，以评估体内对osimertinib的反应。持续口服osimertinib可诱导HER2过表达异种移植瘤初期缩小；然而这些肿瘤随后出现明显复长，而亲本肿瘤则表现出更持久的反应。最后，在HER2过表达的EGFR突变型细胞中，HER2靶向酪氨酸激酶抑制剂与osimertinib联用可协同抑制肿瘤细胞生长。总之，HER2过表达可诱导对osimertinib的获得性耐药，而HER2/EGFR双重阻断可克服这种耐药，突显该方法作为EGFR突变型肺癌一种有前景的治疗策略。

查看英文原文 English abstract

HER2 amplification has been identified in 2-5% of patients with EGFR-mutant lung cancer who have acquired resistance to osimertinib; however, its precise mechanisms in mediating resistance remain unclear. This study aims to elucidate how HER2 aberration contributes to acquired resistance to osimertinib through multiple preclinical approaches. EGFR-mutant cell lines stably overexpressing HER2 were generated by lentiviral transduction using PC9 (EGFR exon 19 deletion) and H1975 (EGFR L858R). Although HER2-overexpressing cells displayed comparable short-term (3-day) sensitivity to osimertinib in vitro relative to empty-vector controls, long-term assays (>7 days) revealed a remarkable increase in resistant colony formation across both HER2-overexpressing models. Next, xenograft models bearing HER2-overexpressing cells were established in nude mice to evaluate in vivo responses to osimertinib. Continuous oral administration of osimertinib induced initial tumor shrinkage in HER2-overexpressing xenografts; however, these tumors subsequently demonstrated pronounced regrowth, whereas parental tumors exhibited more durable responses. Finally, the combination of a HER2-targeted tyrosine kinase inhibitor and osimertinib synergistically suppressed tumor cell growth in HER2-overexpressing EGFR-mutant cells. In conclusion, HER2 overexpression induced acquired resistance to osimertinib, whereas dual HER2/EGFR blockade overcame this resistance, highlighting this approach as a promising therapeutic strategy for EGFR-mutant lung cancer.

利益披露 Disclosure

G. Yamamoto, None.. Y. Tanaka, None.. M. Tsukuda, None.. S. Sayaka, None.. S. Matsui, None. T. Sakai, Amgen ). Ono ). Chugai ). NEC ). AstraZeneca Other, honoraria for lectures. Novartis Other, honoraria for lectures. Thermo Fisher Other, honoraria for lectures. Takeda Other, honoraria for lectures. Olympus Other, honoraria for lectures. Taiho Other, honoraria for lectures. Chugai Other, honoraria for lectures. MSD Other, honoraria for lectures. Merck Other, honoraria for lectures. Daiichi Sankyo Other, honoraria for lectures. Riken Genesis Other, honoraria for lectures. Amco Other, honoraria for lectures. H. Izumi, Amgen ). Eisai ). Takeda ). BMS Japan ). Chugai ). AstraZeneca ). Ono ). MSD ). Merck ). E. Sugiyama, None. Y. Zenke, AstraZeneca ). Daiichi Sankyo ). Amgen ). GSK ). Roche ). MSD ). Merck ). AstraZeneca Other, honoraria for lectures. Lilly Other, honoraria for lectures. Chugai Other, honoraria for lectures. Ono Other, honoraria for lectures. BMS Other, honoraria for lectures. Takeda Other, honoraria for lectures. Boehringer Other, honoraria for lectures. Taiho Other, honoraria for lectures. MSD Other, honoraria for lectures. Novartis Other, honoraria for lectures. Pfizer Other, honoraria for lectures. Nihon Kayaku Other, honoraria for lectures. Kyowa Kirin Other, honoraria for lectures. S. Umemura, Taiho ). Lilly ). MSD ). MSD Other, honoraria for lectures. Chugai Other, honoraria for lectures. Takeda Other, honoraria for lectures. AstraZeneca Other, honoraria for lectures. Daiichi Sankyo Other, honoraria for lectures. K. Yoh, Abbvie ). Amgen ). ArriVent ). AstraZeneca ). Boehringer ). Chugai ). Daiichi Sankyo ). Lilly ). MSD ). Taiho ). Takeda ). Boehringer Ingelheim Other, consulting fees. Abbvie Other, consulting fees. Amgen Other, honoraria for lectures. AstraZeneca Other, honoraria for lectures. BMS Other, honoraria for lectures. Chugai Other, honoraria for lectures. Daiichi Sankyo Other, honoraria for lectures. Kyowa Kirin Other, honoraria for lectures. Lilly Other, honoraria for lectures. K. Goto, Amgen ). Astellas ). AstraZeneca ). Boehringer ). BMS ). Chugai ). Daiichi Sankyo ). Eisai ). Janssen ). Kyowa Kirin ). Merck ). MBL ). MSD ). Novartis ). ONO ). Pfizer ). Sumitomo ). Taiho ). Lilly ). Bayer ). H. Udagawa, Takeda ). Boehringer Ingelheim ). Amgen ). Taiho ). MSD ). Daiichi Sankyo Other, honoraria for lectures. Chugai Other, honoraria for lectures. Novartis Other, honoraria for lectures. Taiho Other, honoraria for lectures. MSD Other, honoraria for lectures.

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