TERT promoter mutations and monoallelic activation of TERT in cancer.

Here we report that promoter mutations in telomerase (TERT), the most common noncoding mutations in cancer, give rise to monoallelic expression of TERT. Through deep RNA sequencing, we find that TERT activation in human cancer cell lines can occur in either mono- or biallelic manner. Without exception, hotspot TERT promoter mutations lead to the re-expression of only one allele, accounting for approximately half of the observed cases of monoallelic TERT expression. Furthermore, we show that monoallelic TERT expression is highly prevalent in certain tumor types and widespread across a broad spectrum of cancers. Taken together, these observations provide insights into the mechanisms of TERT activation and the ramifications of noncoding mutations in cancer.

Targeted cancer therapies in the twenty-first century: lessons from imatinib.

An increased understanding of the molecular etiology of cancer has enabled the development of novel therapies that are collectively referred to as molecular targeted agents. Unlike the drugs used in conventional chemotherapy, these agents are designed to specifically interfere with key molecular events that are responsible for the malignant phenotype. They hold great promise for widening the therapeutic window, which would provide more effective treatment options as compared with cytotoxic therapies. In addition, the targeted approach that is characteristic of these drugs provides unique opportunities for combination therapies with other anticancer agents that have non-overlapping toxicities. Targeted agents are therefore primed to become invaluable therapeutic tools in the multimodal treatment of cancer. The challenges associated with these novel targeted therapies are distinct from those faced in conventional chemotherapy. These unique challenges include the need to select appropriate pharmacodynamic markers to guide dose and schedule and to identify biomarkers that enable selection of patient populations that are most likely to benefit from the treatment. In addition, although the emergence of resistance to targeted therapies is a problem frequently faced in the clinic, the molecular characterization of resistance mechanisms provides the opportunity to design second-generation therapies or combination therapies aimed at preventing resistance or restoring response. The development of the tyrosine kinase inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia (CML). In this article, we discuss the lessons learned from the application of imatinib and other targeted agents in clinical practice and discuss how these insights may guide the development of novel targeted therapies.

Dissecting cancer pathways and vulnerabilities with RNAi.

The latest generation of molecular-targeted cancer therapeutics has bolstered the notion that a better understanding of the networks governing cancer pathogenesis can be translated into substantial clinical benefits. However, functional annotation exists for only a small proportion of genes in the human genome, raising the likelihood that many cancer-relevant genes and potential drug targets await identification. Unbiased genetic screens in invertebrate organisms have provided substantial insights into signaling networks underlying many cellular and organismal processes. However, such approaches in mammalian cells have been limited by the lack of genetic tools. The emergence of RNA interference (RNAi) as a mechanism to suppress gene expression has revolutionized genetics in mammalian cells and has begun to facilitate decoding of gene functions on a genome scale. Here, we discuss the application of such RNAi-based genetic approaches to elucidating cancer-signaling networks and uncovering cancer vulnerabilities.