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Inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs response of cancer cells to DR5-mediated apoptosis and T cell-induced killing

Oncogene volume 35, pages 459–467 (2016)Cite this article

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Abstract

Inhibition of B-Raf/MEK/ERK signaling is an effective therapeutic strategy against certain types of cancers such as melanoma and thyroid cancer. While demonstrated to be effective anticancer agents, B-Raf or MEK inhibitors have also been associated with early tumor progression and development of secondary neoplasms. The ligation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with its receptor, death receptor 5 (DR5), leading to induction of apoptosis, offers a promising anticancer strategy. Importantly, this is also a natural immunosurveillance mechanism against cancer development. We previously demonstrated that activated B-Raf/MEK/ERK signaling positively regulates DR5 expression. Hence, our current work sought to address whether B-Raf/MEK/ERK inhibition and the consequent suppression of DR5 expression impede cancer cell response to DR5 activation-induced apoptosis and activated immune cell-induced killing. We found that both B-Raf (for example, PLX4032) and MEK inhibitors (for example, AZD6244 and PD0325901) effectively inhibited ERK1/2 phosphorylation and reduced DR5 levels in both human thyroid cancer and melanoma cells. Similar to the observed effect of genetic knockdown of the B-Raf gene, pre-treatment of cancer cell lines with either B-Raf or MEK inhibitors attenuated or abolished cellular apoptotic response induced by TRAIL or the DR5 agonistic antibody AMG655 or cell killing by activated T cells. Our findings clearly show that inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs DR5 activation-induced apoptosis and T cell-mediated killing of cancer cells. These findings suggest a potential negative impact of B-Raf or MEK inhibition on TRAIL- or DR5-mediated anticancer therapy and on TRAIL/DR5-mediated immune-clearance of cancer cells.

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Acknowledgements

We are grateful to Drs P Giannakakou, J Arbiser and R Schweppes for providing cancer cell lines and Amgen Inc. for the generous provision of AMG655. We are also thankful to Dr A Hammond for editing the manuscript. This study was supported by the NIH/NCI SPORE P50 grant CA128613 (to S-Y Sun for Project 2) and Emory Winship Cancer Institute Robbins Scholar awards (to Y-T Oh and to J Deng), Melanoma Research Fund (to J Deng) and Halpern Research Scholar award (to S-Y Sun). FR Khuri, TK Owonikoko and S-Y Sun are Georgia Research Alliance Distinguished Cancer Scientists. S-Y Sun is a Halpern Research Scholar.

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  1. Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA

    Y-T Oh, J Deng, P Yue, T K Owonikoko, F R Khuri & S-Y Sun

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  1. Y-T Oh
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  2. J Deng
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Correspondence to S-Y Sun.

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Oh, YT., Deng, J., Yue, P. et al. Inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs response of cancer cells to DR5-mediated apoptosis and T cell-induced killing. Oncogene 35, 459–467 (2016). https://doi.org/10.1038/onc.2015.97

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