Abstract
Elucidating how cancer cells respond to antagonists of HER receptor family members is critical to understanding mechanisms of therapeutic resistance that arise in patients. In large part, resistance to such agents appears to arise from deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway. mTOR-dependent phosphorylation of the translation repressor 4E-BP1 leads to its dissociation from eIF4E, thereby causing an increase in the formation of the eIF4F complex, which also comprises eIF4G and eIF4A. In this study, we show that trastuzumab, cetuximab, and erlotinib all decrease the formation of the eIF4F complex in breast, colon, and head and neck cancer cells, respectively. Ectopic expression of eIF4E restores the trastuzumab-dependent defect in eIF4F formation, renders cells resistant to the trastuzumab-mediated decrease in cell proliferation, and rescues breast cancer xenografts from inhibition by trastuzumab. In breast tumor specimens, the level of eIF4E expression is associated with the therapeutic response to a trastuzumab-based regimen. Together, our findings suggest that formation of the eIF4F complex may be a critical determinant of the response to anticancer drugs that target HER2 and epidermal growth factor receptor.
Highlights
Targeting the members of the HER tyrosine kinase growth factor receptor family, which have been implicated in the development of many human cancers, has been intensely pursued as a major therapeutic strategy in cancer
Because high levels of eukaryotic initiation factor 4E (eIF4E) and phosphorylated 4E-BP1 indicate poor prognosis in breast cancer [6,7,8,9,10], we reasoned that the assembly of the eIF4F complex might be important in understanding the trastuzumab-dependent effects and, more generally, the effects of anticancer drugs targeting the HER family
We evaluated the consequence of trastuzumab treatment on the phosphorylation status of 4E-BP1 in the HER2-overexpressing BT-474 and SK-BR-3 cell lines
Summary
Targeting the members of the HER tyrosine kinase growth factor receptor family, which have been implicated in the development of many human cancers, has been intensely pursued as a major therapeutic strategy in cancer. Trastuzumab (Herceptin, Genentech), a Food and Drug Administration–approved, humanized, anti-HER2 monoclonal antibody that has become the standard of care in HER2-positive breast cancer patients, blocks HER2-dependent activation of intracellular signaling pathways such as the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR cascade, explaining its antiproliferative and apoptotic functions [1]. Almost half of the HER2-positive breast cancers show primary resistance to trastuzumab or become resistant following chronic exposure to trastuzumab This highlights the need to identify predictive factors of response to trastuzumab therapy. Because high levels of eIF4E and phosphorylated 4E-BP1 indicate poor prognosis in breast cancer [6,7,8,9,10], we reasoned that the assembly of the eIF4F complex might be important in understanding the trastuzumab-dependent effects and, more generally, the effects of anticancer drugs targeting the HER family
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