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Author Notes:

Correspondence: Shi-Yong Sun, Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, 1365-C Clifton Road NE, Suite C3088, Atlanta, GA 30322. Phone: (404) 778-2170; Fax: (404) 778-5520; ssun@emory.edu

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.

FR Khuri, TK Owonikoko and S-Y Sun are Georgia Research Alliance Distinguished Cancer Scientists. S-Y Sun is a Halpern Research Scholar.

Subjects:

Research Funding:

This study was supported by the NIH/NCI SPORE P50 grant CA128613 (to S-Y. S. for Project 2) and Emory Winship Cancer Institute Robbins Scholar awards (to Y-T. O. and to J. D.), Melanoma Research Fund (to J. D.) and Halpern Research Scholar award (to S-Y. S.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Oncology
  • Cell Biology
  • Genetics & Heredity
  • RECEPTOR 5 EXPRESSION
  • AZD6244 ARRY-142886
  • BRAF INHIBITORS
  • SORAFENIB
  • CARCINOMA
  • RAF
  • MEK
  • COACTIVATION
  • MUTATIONS
  • MELANOMA

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

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Journal Title:

Oncogene

Volume:

Volume 35, Number 4

Publisher:

, Pages 459-467

Type of Work:

Article | Post-print: After Peer Review

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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© 2016 Macmillan Publishers Limited All rights reserved.

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