Highlights of This Issue

Abstract

AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment- and structure-based approaches. In this study, Yap and colleagues present the preclinical pharmacology of the novel AKT inhibitor CCT128930 and show its effects on appropriate pharmacodynamic biomarkers, both in vitro and in vivo, and promising antitumor efficacy in human tumor xenograft models with PI3K-AKT-mTOR pathway activation. Using CCT128930 as a preclinical tool, they also developed a robust and sensitive, noninvasive pharmacodynamic biomarker assay using hair follicles that is currently being used in a clinical trial of an AKT inhibitor.A large number of methods have been developed for analyzing treatment-induced cellular perturbations via immunofluorescence microscopy. However, very little attention has been devoted to the question of reproducibility across experiments: How does the assessment of phenotype change when a different biologist performs the experiment or when is it repeated months later? The approach described in this work significantly improves reproducibility of results across experiments compared to standard approaches. An extensive survey of cell cycle inhibitors highlights the prevalence of phenotype variability across agents of a given mechanistic class and the occurrence of concentrationdependent changes in phenotypes.Mills and colleagues extend the field of epigenetic therapy to solid tumors focusing on sarcomas and describe a two gene signature that associates with combined histone deacetylase inhibitor and DNA-demethylating treatment. They further validate their predictive results in both cell lines and xenograft mouse models and elucidate that the selective mechanism by which the synergism of these two epigenetic agents is mediated is through inherent differences in chromatin structure. Additionally, they show that these patterns hold true in human sarcomas and may be used to further guide the development of epigenetic agents in sarcomas and other solid tumors.POncogenic KRAS is found in more than 25% of lung adenocarcinomas, the major histologic subtype of non‐small cell lung cancer (NSCLC), and is an important target for drug development. Sunaga and colleagues generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. Their findings suggest that targeting oncogenic KRAS by itself will not be sufficient treatment, but may offer possibilities of combining anti-KRAS strategies with other targeted drugs. Treatment of NSCLCs with KRAS mutations will require knowledge of other tumor molecular abnormalities, which in turn provide additional targeted therapy opportunities for KRAS mutation-positive NSCLC patients.