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针对结直肠肿瘤的 HER3 和 EGFR 的双重靶向治疗可能克服抗 EGFR 耐药性。

Dual targeting of HER3 and EGFR in colorectal tumors might overcome anti-EGFR resistance.

机构信息

Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, 110 72020 Beirut, Lebanon.

Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, 110 72020 Beirut, Lebanon.

出版信息

Crit Rev Oncol Hematol. 2016 May;101:151-7. doi: 10.1016/j.critrevonc.2016.03.009. Epub 2016 Mar 10.

DOI:10.1016/j.critrevonc.2016.03.009
PMID:27017409
Abstract

Multiple genetic alterations have been associated with resistance to anti-EGFR therapy in metastatic colorectal cancer (CRC) patients. Research has been mainly focused on driver mutations in KRAS, NRAS, BRAF and PI3K. However, recent evidence suggests a crucial role for non-genetic mechanisms in conferring resistance to anti-EGFR therapy. Specifically, the HER3 receptor is capable of heterodimerizing with multiple EGFR family members resulting in downstream activation of the PI3K and MAPK pathways. Monoclonal antibodies targeted against the HER3 receptor are being investigated in clinical trials; however, preliminary data has shown limited clinical activity. Thus, given the relevance of the HER3 receptor in activating downstream effector pathways and in conferring resistance to anti-EGFR therapy, the therapeutic targeting of HER3 in combination with primary drivers of the tumor is also being investigated. Here, we review the role of HER3 as a promoter of clinical resistance to EGFR therapy and discuss therapeutic approaches that could potentially overcome this resistance.

摘要

多种基因改变与转移性结直肠癌(CRC)患者对抗 EGFR 治疗的耐药性有关。研究主要集中在 KRAS、NRAS、BRAF 和 PI3K 的驱动突变上。然而,最近的证据表明,非遗传机制在赋予抗 EGFR 治疗耐药性方面起着关键作用。具体而言,HER3 受体能够与多个 EGFR 家族成员异二聚化,导致 PI3K 和 MAPK 途径的下游激活。针对 HER3 受体的单克隆抗体正在临床试验中进行研究;然而,初步数据表明其临床活性有限。因此,鉴于 HER3 受体在激活下游效应子途径以及赋予抗 EGFR 治疗耐药性方面的重要性,也正在研究与肿瘤主要驱动因素联合进行 HER3 的治疗性靶向。在这里,我们回顾了 HER3 作为 EGFR 治疗临床耐药性的促进因子的作用,并讨论了可能克服这种耐药性的治疗方法。

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