Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells
Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells
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DOI：
10.3390/cancers11010105
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发表时间：
2019-01-01
期刊：
影响因子：
5.2
通讯作者：
Tseng, Ling-Ming
中科院分区：
文献类型：
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作者：
Liu, Chun-Yu;Chu, Pei-Yi;Tseng, Ling-Ming
三阴性乳腺癌（TNBC）是一种复杂的疾病，具有侵袭性表型和不良预后。TNBC含有异质分子亚型，没有被批准的特异性靶向治疗。据报道，HER受体在包括TNBC在内的乳腺癌中过度表达。在这项研究中，我们评估了varlitinib（一种可逆的小分子泛her抑制剂）在TNBC中的疗效。我们的研究结果表明，在大多数TNBC细胞系中，伐利替尼降低了细胞活力并诱导细胞凋亡，但在MDA-MB-231细胞中没有。在MDA-MB-231细胞中，MEK和ERK抑制克服了对伐利替尼的耐药性。伐利替尼抑制HER信号通路，抑制MDA-MB-468异种移植小鼠模型TNBC细胞的迁移、侵袭和乳腺球形成，显著抑制肿瘤生长。总之，这些结果表明HER信号在TNBC的进展中起着重要作用，泛HER抑制可能是TNBC患者的有效治疗方法。
Triple-negative breast cancer (TNBC) is a complex disease associated with the aggressive phenotype and poor prognosis. TNBC harbors heterogeneous molecular subtypes with no approved specific targeted therapy. It has been reported that HER receptors are overexpressed in breast cancer including TNBC. In this study, we evaluated the efficacy of varlitinib, a reversible small molecule pan-HER inhibitor in TNBC. Our results showed that varlitinib reduced cell viability and induced cell apoptosis in most TNBC cell lines but not in MDA-MB-231 cells. MEK and ERK inhibition overcame resistance to varlitinib in MDA-MB-231 cells. Varlitinib inhibited HER signaling which led to inhibition of migration, invasion and mammosphere formation of TNBC cells as well as significant suppression of tumor growth of MDA-MB-468 xenograft mouse model. In summary, these results suggest that HER signaling plays an important role in TNBC progression and that pan-HER inhibition is potentially an effective treatment for TNBC patients.