Title:Novel Targeted Therapies to Overcome Trastuzumab Resistance in HER2- Overexpressing Metastatic Breast Cancer
Volume: 14
Issue: 8
Author(s): Yuan Huang, Peifen Fu and Weimin Fan
Affiliation:
Keywords:
HER2-overexpressing MBC, trastuzumab resistance, TKIs, mAbs, HER2 vaccines, bsAbs.
Abstract: Overexpression of the human epidermal growth factor receptor 2 (HER2) is identified in approximately 25-
30% of breast cancers and indicates a poor prognosis. Trastuzumab, the anti-HER2 monoclonal antibody (mAb), has
shown significant clinical effects selectively in HER2-overexpressing metastatic breast cancer (MBC) with improved
overall survival and reduced recurrent risk. However, there is an urgent need to develop new strategies to overcome innate
and acquired trastuzumab resistance, which has increasingly occurred. Recently, an increased understanding of mechanisms
of trastuzumab resistance significantly promotes the development of novel targeted therapies for trastuzumabrefractory
disease. It is believed that aberrant activations of several signaling pathways involving the human epidermal
growth factor receptor (EGFR/HER) family, phosphoinositide 3 kinase/Akt (PI3K/Akt) pathway, and vascular endothelial
growth factor (VEGF) family, contribute to the development of trastuzumab resistance. Novel agents that target these
relevant signal pathways provide some potential solutions, such as tyrosine kinase inhibitors (TKIs) and mAbs. HER2 is
also recognized as an immunotherapeutic target. The failure to induce immune-mediated antitumor response is another
important reason for trastuzumab resistance. Strategies to boost T cell-mediated immune responses specific to HER2 including
HER2 vaccines and bispecific antibodies (bsAbs) could be developed as a promising way to prevent relapse or
combat trastuzumab resistance. In this review, the emerging data from preclinical and clinical studies related to these
novel therapies will be discussed.
