Trastuzumab-Resistance and Breast Cancer

Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition

“…39,40 While downregulation of Akt is believed to be one of the major mechanisms of action of trastuzumab, trastuzumab is still capable of inhibiting Akt activity in trastuzumab-resistant JIMT1 breast cancer cells. This finding indicates that resistance to trastuzumab may not be due to the inability of trastuzumab to inhibit Akt activity.…”

Mechanisms of Trastuzumab Resistance and Opportunities to Overcome Therapeutic Resistance

“…Trastuzumab is a humanized monoclonal antibody directed against extracellular domain IV of Human Epidermal Growth Factor Receptor 2 (HER2) and is approved for the treatment of HER2-positive breast cancers either alone or in combination with chemotherapeutic agents [1,2]. HER2 is a member of HER/ErbB family of receptor tyrosine kinases, which play important role in breast cancer development and progression [1].…”

“…Over the past two decades, the development of monoclonal antibodies targeting HER2 has been intensely pursued as important cancer therapeutic strategy. While treatment with trastuzumab very successfully improves outcomes for women with HER2-positive breast cancer, therapeutic resistance to trastuzumab, including primary and acquired resistance, pose a significant hurdle in the treatment of HER2-positive breast cancers [2,6,7], Better understanding of molecular mechanisms underlying primary or acquired resistance to trastuzumab is critical to improving the survival of patients with HER2-positive breast cancer.…”

“…Based on cell culture, xenograft models and clinical studies, mechanisms of trastuzumab resistance can be generally grouped as either related to the aberrant HER2 receptor signaling at the cell surface or to the deregulated signaling of the intracellular molecular players downstream of HER2 receptor [2]. The examples of the aberrant HER2 signaling at the cell surface include expression of p95HER2 truncated form which lacks the extracellular trastuzumab-binding domain [8], overexpression of MUC4 glycoprotein on the cell surface, which blocks trastuzumab binding site on HER2 [9], increased heterodimerization of HER2 with other HER family members such as HER1/EGFR [10] or with other receptor tyrosine kinases such as IGF-IR [11].…”

“…Tyrosine kinase inhibitors (TKIs), such as neratinib and lapatinib, are tested either alone or in combination with trastuzumab for trastuzumab-resistant disease [18,19]. Small molecular inhibitors targeting PI3K (XL147 and BKM120), mTOR (everolimus and temsirolimus) and Hsp90 (tanespymicin) are also tested in Phase I and II clinical studies in trastuzumab-resistant breast cancer [2,20,21]. Combination of trastuzumab with another monoclonal antibody, which targets different epitope on HER2-pertuzumab is currently under clinical evaluation for the treatment of trastuzumab-resistant disease [22,23].…”