Formation of the eIF4F Translation–Initiation Complex Determines Sensitivity to Anticancer Drugs Targeting the EGFR and HER2 Receptors

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. mTORdependent 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 trastuzumabdependent 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. Cancer Res; 71(12); 4068-73. Ó2011 AACR.

ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer

“…Conversely, aberrant activation of translation by eIF4E amplification or 4E-BP1 reduction has the opposite effect and profoundly attenuates dependence of CRC cells on the ERK and AKT signaling for migration and invasion. Given that deregulation of cap-dependent translation due to overexpression of eIF4E or loss of 4E-BP1 function often occurs in CRC 15–18 and has been shown to cause resistance to inhibition of upstream oncogenic signals, 34–36 our findings suggest that directly targeting the convergence of ERK and AKT signaling on translation initiation may be an effective alternative to combination of both kinase inhibitors in advanced and disseminated CRC. Validation of this hypothesis requires additional clinical correlative studies and awaits the development of clinically effective inhibitions of translation initiation.…”

TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis

“…This coincides with the fact that targeting translation for an efficient anti-cancer therapy is now a reality, as illustrated with mammalian target of rapamycin targeting. 43 The impact on translation initiation of presently used anti-cancer therapy starts also to be demonstrated, 44,45 signifying the importance that translation has in cancer. Reverse transcriptase-qPCR analysis RNA was extracted using TRIzol reagent (Life Technologies) according to the manufacturer's instructions and treated by DNase I (Fisher Scientific, Illkirch-Graffenstaden, France).…”

Hepatitis C Virus NS5A Binds to the mRNA Cap-binding Eukaryotic Translation Initiation 4F (eIF4F) Complex and Up-regulates Host Translation Initiation Machinery through eIF4E-binding Protein 1 Inactivation

“…Many of these proteins are involved in events such as cell cycle regulation, apoptosis, and angiogenesis (35)(36)(37)(38). Some recent reports support the implicated role of enhanced eIF4F complex assembly on cancer development and drug resistance (39,40).…”