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

• Published in: Oncogene 2016-01, Vol.35 (4), p.459-467
• Main Authors: Oh, Y-T, Deng, J, Yue, P, Owonikoko, T K, Khuri, F R, Sun, S-Y
• Format: Article
• Language: English
• Subjects: 13; 13/2; 13/21; 13/95; 631/67/1059/602; 96; 96/31; Apoptosis; Apoptosis - drug effects; Benzimidazoles - pharmacology; Cancer; Cancer therapies; Carcinogenesis; Cell Biology; Cell Line, Tumor - drug effects; Cellular signal transduction; Enzyme Inhibitors - pharmacology; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene expression; Genetic aspects; Health aspects; Human Genetics; Humans; Indoles - pharmacology; Internal Medicine; Kinases; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Medicine; Medicine & Public Health; Oncology; original-article; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; RNA, Small Interfering; Signal Transduction - drug effects; Sulfonamides - pharmacology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; TNF-Related Apoptosis-Inducing Ligand - metabolism; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.97

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.