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癌症以外的HER2靶向治疗-更新

HER2-targeted therapies beyond breast cancer — an update

Nature 等信源发布 2024-07-22 03:01

可切换为仅中文


AbstractThe receptor tyrosine-kinase HER2 (also known as ErbB2) is a well-established therapeutic target in patients with breast or gastric cancer selected on the basis of HER2 overexpression on immunohistochemistry and/or ERBB2 amplification on in situ hybridization. With advances in cancer molecular profiling and increased implementation of precision medicine approaches into oncology practice, actionable HER2 alterations in solid tumours have expanded to include ERBB2 mutations in addition to traditional HER2 overexpression and ERBB2 amplification.

摘要受体酪氨酸激酶HER2(也称为ErbB2)是基于免疫组织化学上HER2过表达和/或原位杂交上ErbB2扩增而选择的乳腺癌或胃癌患者的公认治疗靶点。随着癌症分子谱分析的进步以及精准医学方法在肿瘤学实践中的应用越来越多,实体瘤中可行的HER2改变已经扩展到除了传统的HER2过表达和ERBB2扩增之外还包括ERBB2突变。

These various HER2 alterations can be found in solid tumour types beyond breast and gastric cancer, although few HER2-targeted therapeutic options have been established for the other tumour types. Nevertheless, during the 5 years since our previous Review on this topic was published in this journal, obvious and fruitful progress in the development of HER2-targeted therapies has been made, including new disease indications, innovative drugs with diverse mechanisms of action and novel frameworks for approval by regulatory authorities.

这些不同的HER2改变可以在乳腺癌和胃癌以外的实体瘤类型中发现,尽管对于其他肿瘤类型几乎没有针对HER2的治疗选择。尽管如此,自我们之前在本期刊上发表关于这一主题的评论以来的5年中,在开发HER2靶向疗法方面取得了明显而富有成效的进展,包括新的疾病适应症,具有多种作用机制的创新药物和新的框架供监管机构批准。

These advances have culminated in the recent histology-agnostic approval of the anti-HER2 antibody–drug conjugate trastuzumab deruxtecan for patients with HER2-overexpressing solid tumours. In this new Review, we provide an update on the current development landscape of HER2-targeted therapies beyond breast cancer, as well as anticipated future HER2-directed treatment strategies to overcome resistance and thereby improve efficacy and patient outcomes.Key points.

这些进展最终导致抗HER2抗体-药物偶联物曲妥珠单抗-德鲁替康治疗HER2过表达实体瘤患者的组织学不可知批准。在这篇新的综述中,我们提供了乳腺癌以外HER2靶向治疗的当前发展前景的最新信息,以及预期的未来HER2导向治疗策略,以克服耐药性,从而提高疗效和患者预后。关键点。

Over the past few years, the indications for HER2-targeted therapy have expanded beyond breast cancer and gastric or gastroesophageal junction cancer (G/GEJC) to include various other solid tumour types.

在过去的几年中,HER2靶向治疗的适应症已经扩展到乳腺癌和胃或胃食管交界癌(G/GEJC)之外,以包括各种其他实体瘤类型。

The anti-HER2 antibody–drug conjugate trastuzumab deruxtecan has become a new standard of care for patients with treatment-refractory HER2-positive G/GEJC, HER2-mutant non-small-cell lung cancer or any HER2-overexpressing (immunohistochemistry 3+) solid tumour, owing to its potent antitumour activity and impressive clinical efficacy..

抗HER2抗体-药物偶联物曲妥珠单抗-德鲁替康已成为治疗难治性HER2阳性G/GEJC,HER2突变型非小细胞肺癌或任何HER2过表达(免疫组织化学3+)实体瘤患者的新标准治疗,因为它具有强大的抗肿瘤活性和令人印象深刻的临床疗效。。

Ten years after the ToGA study established the anti-HER2 antibody trastuzumab in combination with chemotherapy as the standard of care for patients with previously untreated advanced-stage HER2-positive G/GEJC, the addition of an immune-checkpoint inhibitor (the anti-PD-1 antibody pembrolizumab) to this regimen has presented a new first-line treatment option for this disease..

ToGA研究确定抗HER2抗体曲妥珠单抗联合化疗作为先前未经治疗的晚期HER2阳性G/GEJC患者的标准治疗十年后,在该方案中加入免疫检查点抑制剂(抗PD-1抗体pembrolizumab)为该疾病提供了一种新的一线治疗选择。。

Several potential mechanisms of resistance to HER2-targeted therapies have been identified, such as alterations that impaired drug binding to HER2 or that constitutively activate signalling pathways downstream of or parallel to HER2.

已经确定了几种针对HER2靶向治疗的潜在耐药机制,例如损害药物与HER2结合或组成性激活HER2下游或平行于HER2的信号传导途径的改变。

Novel agents targeting HER2 and new combinations HER2-target therapies with various agents, including inhibitors of other receptor tyrosine kinases, immunotherapies and DNA damage repair inhibitors, are under investigation in clinical trials.

靶向HER2的新型药物和HER2靶向治疗与各种药物的新组合,包括其他受体酪氨酸激酶抑制剂,免疫疗法和DNA损伤修复抑制剂,正在临床试验中进行研究。

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Access Nature and 54 other Nature Portfolio journalsGet Nature+, our best-value online-access subscription24,99 € / 30 dayscancel any timeLearn moreSubscription info for Chinese customersWe have a dedicated website for our Chinese customers. Please go to naturechina.com to subscribe to this journal.Go to naturechina.comBuy this articlePurchase on Springer LinkInstant access to full article PDFBuy nowPrices may be subject to local taxes which are calculated during checkout.

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Fig. 1: Frequency of HER2 alterations across tumour types.Fig. 2: Distribution of oncogenic HER2 mutations along the ERBB2 gene across tumour types.Fig. 3: Mechanisms of action of various HER2-targeted antibodies, tyrosine-kinase inhibitors and antibody–drug conjugates.Fig. 4: Mechanisms of action of various HER2-targeted T cell engagers, immunostimulatory antibody conjugates and cell therapies..

图1:HER2在肿瘤类型中改变的频率。图2:沿着ERBB2基因的致癌HER2突变在肿瘤类型中的分布。图3:各种HER2靶向抗体,酪氨酸激酶抑制剂和抗体-药物偶联物的作用机制。图4:各种HER2靶向T细胞参与者,免疫刺激性抗体缀合物和细胞疗法的作用机制。。

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Download referencesAcknowledgementsThe work of the authors is supported by a National Research Foundation of Korea grant funded by the Korea government (MSIT; grant no. 2021R1A2C2007430 to D.-Y.O.) and the Institute of Smart Healthcare Innovative Medical Sciences, a Brain Korea 21 four programme, Seoul National University (to D.-Y.O.).Author informationAuthors and AffiliationsDivision of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of KoreaJeesun Yoon & Do-Youn OhCancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of KoreaDo-Youn OhIntegrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of KoreaDo-Youn OhAuthorsJeesun YoonView author publicationsYou can also search for this author in.

下载参考文献致谢作者的工作得到了韩国政府资助的韩国国家研究基金会(MSIT;授予D.Y.O.的授权号2021R1A2C2007430)和首尔国立大学智能医疗创新医学科学研究所(Brain Korea 21 four Program,首尔国立大学)的支持。作者信息作者和附属机构首尔国立大学医院内科肿瘤内科,韩国首尔国立大学医学院,韩国首尔国立大学医学院,韩国首尔国立大学医学院,韩国首尔国立大学研究生院,韩国首尔国立大学研究生院,韩国首尔国立大学研究生院,韩国首尔国立大学医学院,韩国首尔国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立大学医学院,韩国国立。

PubMed Google ScholarDo-Youn OhView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsThe authors contributed equally to all aspects of the article.Corresponding authorCorrespondence to

PubMed谷歌学术贡献作者对文章的各个方面都做出了同样的贡献。对应作者对应

Do-Youn Oh.Ethics declarations

别这样哦。道德宣言

Competing interests

相互竞争的利益

D.-Y.O. has acted as a consultant or adviser for Abbvie, Arcus Biosciences, ASLAN, Astellas, AstraZeneca, Basilea, Bayer, BeiGene, Bristol Myers Squibb/Celgene, Eutilex, Genentech/Roche, Halozyme, Idience, IQVIA, J-Pharma, LG Chem, Merck Serono, Mirati Therapeutics, Moderna, MSD, Novartis, Taiho, Turning Point, Yuhan and Zymeworks, and has received research grants from Array, AstraZeneca, BeiGene, Eli Lilly, Handok, MSD, Novartis and Servier.

D、 -Y.O.曾担任Abbvie,Arcus Biosciences,ASLAN,Astellas,AstraZeneca,Basilea,Bayer,BeiGene,Bristol-Myers Squibb/Celgene,Eutilex,Genentech/Roche,Halozyme,Idience,IQVIA,J-Pharma,LG Chem,Merck Serono,Mirati Therapeutics,Moderna,MSD,Novartis,Taiho,Turning Point,Yuhan和Zymeworks的顾问或顾问,并获得了Array,AstraZeneca,BeiGene,Eli Lilly,Handok,MSD,Novartis和Servic的研究资助呃。

J.Y. declares no competing interests..

J、 Y.声明没有利益冲突。。

Peer review

同行评审

Peer review information

同行评审信息

Nature Reviews Clinical Oncology thanks F. Lordick, M. Nagasaka, A. Sartore-Bianchi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

《自然评论》临床肿瘤学感谢F.Lordick,M.Nagasaka,A.Sartore Bianchi和另一位匿名审稿人对这项工作的同行评审做出的贡献。

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HER2-targeted therapies beyond breast cancer — an update..

HER2靶向治疗超越乳腺癌-最新进展。。

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