Mechanisms Behind the Resistance to Trastuzumab in HER2-Amplified Breast Cancer and Strategies to Overcome It

Abstract

The introduction of trastuzumab therapy markedly improved the poor prognosis associated with HER2-amplified breast cancers. Despite this, the presence of primary and acquired resistance to trastuzumab treatment remains a significant common challenge. The identification of resistance mechanisms and the incorporation of new drugs that achieve a better blockade of HER family receptors signaling have resulted in improved outcomes. The phosphatidylinositol 3'-kinase/protein kinase B/mammalian target of rapamycin pathway, cross-talk with estrogen receptors, immune response, cell cycle control mechanisms, and other tyrosine kinase receptors such as insulin-like growth factor I receptor are potential pathways involved in trastuzumab resistance. Different therapeutic interventions targeting these pathways are currently under evaluation.

Keywords: HER2 overexpression; biomarker; breast cancer; resistance; trastuzumab.

Figure 1

Signal transduction by HER2 dimerization.

Figure 2

Mechanisms of resistance to trastuzumab. Abbreviations: Akt, protein kinase B; Cdk 2/4, cyclin-dependent kinase 2/4; E2, estradiol; ER, estrogen receptor; IGF1R, insulin-like growth factor I receptor; HER, human epidermal growth factor receptor; MAPK, Mitogen-activated protein kinases; mTOR, mammalian target of rapamycin; P, phosphorylation; PI3K, phosphatidylinositol 3′-kinase; PI3Kmut, mutated phosphatidylinositol 3′-kinase; PTEN, phosphatase and tensin homolog.