Highlights of This Issue

Abstract

The role of G-protein coupled–receptors (GPCR) in cancer and how to best target their function remains incompletely understood. Using The Cancer Genome Atlas, primary tumor specimens, and in vitro studies, Woerner and coworkers found that expression of G-protein coupled–receptor kinases (GRK), critical regulators of GPCR function, is altered in glioblastoma in a molecular subtype–specific fashion. Decreased GRK3 expression in classical glioblastoma was associated with a growth advantage, which was blocked by reconstitution of GRK3 expression. These data indicate that GPCRs function to regulate glioblastoma growth and suggest that modulation of GPCR phosphorylation may be an important therapeutic strategy.The antioxidant enzyme extracellular superoxide dismutase EcSOD is downregulated in a large proportion of human lung cancers. To explore its role in cancer, Teoh-Fitzgerald and colleagues examined EcSOD gene expression, as well as the biological effects of its reexpression in EcSOD-negative tumor cells. Epigenetic silencing by aberrant cytosine methylation of the promoter was the most frequent cause of expression loss in human lung adenocarcinoma compared with normal lung. Reexpression of EcSOD inhibited the in vitro invasiveness of human lung adenocarcinoma cells. This study identifies EcSOD as an epigenetically regulated lung cancer target and a modifier of the malignant phenotype.TRAIL induces apoptosis in basal/triplenegative breast cancer (TNBC) cell lines, whereas other subtypes are relatively resistant. Inhibition of WEE1, a cell-cycle checkpoint regulator, causes increased cell death in cancer cell lines. Here, Garimella and colleagues show that pretreatment with WEE1 inhibitor increased the toxicity of TRAIL in TNBC cell lines. This effect is attributed to increased surface expression of death receptors resulting in increased caspase activation initiated by caspase-8. These data suggest that the combination of WEE1 inhibitor and TRAIL could provide a novel approach to targeted therapy for TNBC.Although largely unknown, the abnormalities in DNA repair that underlie the genomic instability in sporadic cancers are potential therapeutic targets. Tobin and colleagues have characterized a novel defect in DNA double-strand break repair in hormone therapy–resistant breast cancer that can be identified in breast cancer cell lines and tumor biopsies and can be selectively targeted by a combination of PARP and DNA ligase inhibitors. These preclinical studies provide the rationale for the development of effective therapeutic strategies for hormone therapy–resistant breast cancer that may be applicable to other cancers, including leukemias, with similar DNA repair abnormalities.