HER2-directed T-cell receptor-mimicking antibody: A me too or an example of novel antitumor aggressive mimicry?

摘要

Targeting the erbB2 receptor protein (HER2) has been one of the most successful stories of oncology drug therapy in the past 10 years. HER2 overexpression or gene amplification is a "driver" alteration to which approximately 20% of breast cancers are addicted. The potent proliferative and antiapoptotic signals that aberrant expression of HER2 confers to tumors (1) are associated with a clinical aggressive phenotype and poor prognosis (2,3) and have justified extensive pharmacological research to target HER2. The success of the humanized monoclonal antibody trastuzumab in HER2-positive breast cancer as therapy of metastatic stages (4) or as adjuvant or neoadjuvant treatment of operable tumors (5-7) rapidly led to a dramatic improvement of the outcome of the disease (8). The paradigm that a proportion of tumors are addicted to HER2 and susceptible to HER2-directed therapy is now being extended to a proportion of carcinomas of the gastroesophageal junction, in which trastuzumab and chemotherapy resulted in statistically significantly prolonged survival (9), and holds promise of wider therapeutic applicability, including to some relapsed, cetuxi-mab-resistant colorectal cancers (10).