Intrinsic and Acquired Resistance to HER2-Targeted Therapies in HER2 Gene-Amplified Breast Cancer: Mechanisms and Clinical Implications

Abstract

Approximately 25% of human breast cancers overexpress the HER2 (ErbB2) proto-oncogene, which confers a more aggressive tumor phenotype and associates with a poor prognosis in patients with this disease. Two approved therapies targeting HER2, the monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib, are clinically active against this type of breast cancer. However, a significant fraction of patients with HER2+ breast cancer treated with these agents eventually relapse or develop progressive disease. This suggests that tumors acquire or possess intrinsic mechanisms of resistance that allow escape from HER2 inhibition. This review focuses on mechanisms of intrinsic and/or acquired resistance to HER2-targeted therapies that have been identified in preclinical and clinical studies. These mechanisms involve alterations to HER2 itself, coexpression or acquisition of bypass signaling through other receptor or intracellular signaling pathways, defects in mechanisms of cell cycle regulation or apoptosis, and host factors that may modulate drug response. Emerging clinical evidence already suggests that combinations of therapies targeting HER2 as well as these resistance pathways will be effective in overcoming or preventing resistance.

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

“…It suggests that the mutant gene may not be associated with real amplification 95. In fact, insufficient evidence about the mutations in HER‐2 ‘positive’ can be searched.…”

Molecular biology of human epidermal receptors, signaling pathways and targeted therapy against cancers: new evidences and old challenges

“…Despite responses to treatment with trastuzumab for HER2-positive tumors, relapses after early responses were observed in 50-66% of HER2-positive patients (Rexer, Arteaga, 2012). When resistance has occurred, there is no effective drug able to block the progression of the disease.…”

delta16HER2 splice variant and its role in HER2-overexpressing breast cancer

“…In particular, the humanized monoclonal antibody (MAb) T binds to the juxtamembrane region (subdomain IV) of HER2ECD and has been approved in combination with chemotherapy as the standard of care for HER2-positive metastatic BC, in early disease and also, very recently, in the neo-adjuvant setting De et al, 2013). Although T administration induces significant clinical benefits in a consistent number of patients, tumors progress in a high percentage of cases after one year of treatment and develop de novo or acquired resistance (Rexer and Arteaga, 2012;Wong and Lee, 2012). Potential resistance mechanisms, including activation of compensatory signal transduction pathways (HER2 cross-talk with other RTKs and amplification of HER signaling and/or alterations of the PI3K/AKT pathway) or defects in apoptosis and cell cycle control, have been demonstrated in in vitro models (Rexer and Arteaga, 2012) but await clinical validation.…”

“…Although T administration induces significant clinical benefits in a consistent number of patients, tumors progress in a high percentage of cases after one year of treatment and develop de novo or acquired resistance (Rexer and Arteaga, 2012;Wong and Lee, 2012). Potential resistance mechanisms, including activation of compensatory signal transduction pathways (HER2 cross-talk with other RTKs and amplification of HER signaling and/or alterations of the PI3K/AKT pathway) or defects in apoptosis and cell cycle control, have been demonstrated in in vitro models (Rexer and Arteaga, 2012) but await clinical validation. Interestingly, recent preclinical studies suggest that HER2-overexpressing tumors able to evade T activity continue to exert HER2 oncogenic action as they retain HER2 amplification and overexpression (Hurvitz et al, 2013;Krop and Burstein, 2013).…”

“…Interestingly, recent preclinical studies suggest that HER2-overexpressing tumors able to evade T activity continue to exert HER2 oncogenic action as they retain HER2 amplification and overexpression (Hurvitz et al, 2013;Krop and Burstein, 2013). A significant contribution to T resistance could also derive from genetic or molecular events that lead to an increase in HER2 oncogenic potential and/or influence T binding to the receptor (Rexer and Arteaga, 2012). Indeed, different isoforms of the HER2 receptor have been identified in human BC deriving from alternative initiation of translation or splicing and proteolytic shedding (Table 1) and are not recognized by the humanized antibody (Arribas et al, 2011;Garrett and Arteaga, 2011;Rexer and Arteaga, 2012).…”