Highlights of This Issue

Abstract

To realize the potential of targeted therapy for lung cancer we need to greatly expand our understanding of the genetic alterations that drive tumor growth. Sleeping Beauty (SB) mutagenesis was used by Dorr and colleagues to probe the genome in an unbiased fashion to uncover genetic drivers of lung cancer. These data will help guide development of novel targeted therapies to bolster our arsenal for combatting the most deadly cancer in the United States. Importantly, this article highlights the finding that alterations in the oxidative response pathway contribute to tumorigenesis. This study suggests that newly developed therapeutic agents that target cellular redox regulation may be effective in treating lung cancer.Ovarian carcinomas frequently inactivate p53, are challenging to treat, and commonly become resistant to standard chemotherapy. Nutlin, a drug designed to restore p53 activity by inhibiting its binding to Mdm2 protein, also increases Mdm2 levels. Carrillo and colleagues show that Nutlin stabilizes Mdm2, resulting in inhibition of DNA damage signaling and delayed DNA break repair mediated by Nbs1 of the Mre11–Nbs1–Rad50 DNA repair complex. When Nutlin was combined with genotoxic agents, a cooperative effect resulted in increased apoptosis of ovarian cancer cells with inactive p53. Thus, pharmacologically increasing Mdm2 levels together with chemotherapy is therapeutically beneficial for treating cancers that lack functional p53.The impact of somatic mutations on regulation at gene promoters in cancer has not been systematically evaluated. Poulos and colleagues assessed the influence of promoter mutations on promoter activity in whole-genome sequenced melanoma cells. The study revealed a high number of promoter mutations, many of which significantly altered promoter activity using validation assays. Interestingly, and supporting a potentially pathological role, one mutation within the promoter of the metabolic gene NDUFB9 is recurrent in a subset of melanomas and co-occurs with coding NF1 mutations. This study reveals frequent functional cis-regulatory mutations in cutaneous melanomas, highlighting the need to examine their role in tumorigenesis to find therapeutic targets.Colorectal cancer is one of the most prevalent cancer types worldwide, and K-Ras mutations are a common feature of this type of cancer. Steven and colleagues identify a significant correlation between K-RasV12 mutation and activation of the transcription factor CREB. Targeting CREB activity with small-molecule inhibitors and by shRNAs reduced the neoplastic properties of the cells. Mechanistically, the in vivo tumorigenicity of the K-RasV12-transformed cells was reduced after CREB silencing, but the altered pattern was dependent on the immunogenicity of the animals. Therefore, CREB represents a promising therapeutic target for colorectal cancer using small-molecule inhibitors alone or in combination with immunotherapy.