Emerging insights into mechanisms of trastuzumab resistance in HER2-positive cancers

HER2 is an established therapeutic target in breast, gastric, and gastroesophageal junction carcinomas with HER2 overexpression or genomic alterations. The humanized monoclonal antibody trastuzumab targeting HER2 has substantially improved the clinical outcomes of HER2-positive patients, yet the inevitable intrinsic or acquired resistance to trastuzumab limits its clinical benefit, necessitating the elucidation of resistance mechanisms to develop alternate therapeutic strategies. This review presents an overview of trastuzumab resistance mechanisms involving signaling pathways, cellular metabolism, cell plasticity, and tumor microenvironment, particularly discussing the prospects of developing rational combinations to improve patient outcomes.

Automated summary

HER2 is a therapeutic target in various types of cancer with HER2 overexpression or genomic alterations. Trastuzumab, a humanized monoclonal antibody targeting HER2, has improved the clinical outcomes of HER2-positive patients. However, resistance to trastuzumab poses a challenge, and this review explores the mechanisms of resistance and discusses potential strategies for improving patient outcomes through rational combinations.