Activating HER2 mutations as emerging targets in multiple solid cancers.
Activating HER2 mutations as emerging targets in multiple solid cancers.
复制标题
DOI：
10.1136/esmoopen-2017-000279
复制
发表时间：
2017
期刊：
影响因子：
7.3
通讯作者：
Doherty GJ
中科院分区：
文献类型：
--
作者：
Connell CM;Doherty GJ
跨膜受体酪氨酸激酶的表皮生长因子受体（EGFR）家族激活调节细胞增殖和存活的信号传导途径。HER2是该家族的非配体结合成员，并通过与其他EGFR家族成员的异源二聚化发挥其活性。HER2功能激活促进肿瘤发生，导致研究HER2靶向药物在HER2改变的癌症中的作用。这在乳腺癌和胃食管癌中HER2基因扩增的背景下得到了最好的表征，HER2导向药物是标准治疗方案的一部分。最近，已在一系列人类癌症类型中检测到体细胞HER2基因突变。临床前数据表明，功能性激活HER2突变可能以类似于HER2基因扩增的方式驱动和维持癌症，并且HER2突变可能类似地赋予对HER2靶向药物的敏感性。在这里，我们批判性地回顾了HER2突变型癌症中HER2靶向药物的新作用。我们回顾了实验模型的数据，我们对HER2突变激活的基础生物学知识仍然不完整。我们讨论了I期和II期临床试验的临床数据，这些临床试验评估了HER2靶向药物（酪氨酸激酶抑制剂和基于抗体的药物）在几种癌症类型中的作用。我们强调人类癌症中HER2突变的异质性，癌症类型之间HER2靶向药物临床疗效的差异以及原发性和获得性耐药的可能机制，以指导临床实践和未来的药物开发。
The epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases activates signalling pathways regulating cellular proliferation and survival. HER2 is a non-ligand-binding member of this family and exerts its activity through heterodimerisation with other EGFR family members. HER2 functional activation promotes oncogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 alterations. This has been best characterised in the context of HER2 gene amplification in breast and gastro-oesophageal cancers, for which HER2-directed drugs form part of standard treatment regimens. More recently, somatic HER2 gene mutations have been detected in a range of human cancer types. Preclinical data suggest that functionally activating HER2 mutations may drive and maintain cancers in a manner analogous to HER2 gene amplification and that HER2 mutations may similarly confer sensitivity to HER2-directed drugs. Here, we critically review the emerging roles for HER2-directed drugs in HER2 mutant cancers. We review data from experimental models, where our knowledge of the underlying biology of HER2 mutational activation remains incomplete. We discuss clinical data from Phase I and II clinical trials which evaluate HER2-directed agents (tyrosine kinase inhibitors and antibody-based drugs) in several cancer types. We highlight the heterogeneity of HER2 mutations in human cancers, differences in the clinical efficacy of HER2-directed drugs between cancer types and possible mechanisms of primary and acquired resistance, in order to guide clinical practice and future drug development.
登录
查看更多内容
影响因子：
--
作者：
de Melo Gagliato D;Jardim DL;Marchesi MS;Hortobagyi GN
通讯作者：
Hortobagyi GN
影响因子：
3.9
作者：
Jørgensen JT;Hersom M
通讯作者：
Hersom M
DOI：
10.1097/jto.0b013e31827ce38e
发表时间：
2013-02
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Falchook GS;Janku F;Tsao AS;Bastida CC;Stewart DJ;Kurzrock R
通讯作者：
Kurzrock R
DOI：
10.1158/1078-0432.ccr-12-0912
发表时间：
2012-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arcila ME;Chaft JE;Nafa K;Roy-Chowdhuri S;Lau C;Zaidinski M;Paik PK;Zakowski MF;Kris MG;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
5.7
作者：
Gonzales, Andrea J.;Hook, Kenneth E.;Vincent, Patrick W.
通讯作者：
Vincent, Patrick W.