曲妥珠单抗治疗HER2阳性乳腺癌的耐药机制及新疗法探索

The mechanism of HER2-amplified breast cancer with trastuzumab resistance and the research for novel therapy

研究表明大约有20%的乳腺癌患者存在HER2过表达现象。HER2的异常表达及异常信号通路与乳腺癌的侵袭转移、治疗抵抗及不良预后密切相关。在临床上,对于HER2阳性的初期乳腺癌患者常联合曲妥珠单抗及化学药物治疗,但部分患者对曲妥珠单抗产生耐药。因此,研究其耐药机制对于HER2阳性乳腺癌患者的治疗、预后及新疗法的探索具有重要的临床意义。目前引起曲妥珠单抗抵抗的主要机制有:p95-HER2累积、PI3K/AKT/mTOR信号异常激活、HER家族受体和IGF-1R信号增加、非受体酪氨酸激酶c-SRC活性增加等。将对上述机制及治疗HER2阳性乳腺癌的新疗法进行综述。

Research showed that about 20% breast cancer patients had an over-expression of HER2. Abnormal expressions of HER2 and signal pathway abnormalities are closely associated with breast cancer invasion and metastasis, treatment resistance, and poor prognosis. Clinically, HER2-positive patients in early stages of cancer are often treated with a combination of trastuzumab and chemotherapy, but a portion of patients develop a resistance to trastuzumab. Therefore, there are important clinical implications for the study of resistance mechanisms on HER2- positive breast cancer patients undergoing active treatment and prognosis and the exploration of new therapies. Current important mechanisms that are possible factors to trastuzumab resistance include the accumulation of HER2 truncated mutation in p95-HER2, the upregulation of the PI2K/AKT/mTOR signaling pathway, signal increases of HER receptor families and IGF-1R, and the increase of c-SRC activation. This article will summarize the above mechanisms and new therapies for treating HER2-positive breast cancer.