Review Articles in 2010

The protein tyrosine phosphatase (Ptp) family dephosphorylates target proteins and counters the activities of protein tyrosine kinases. Accumulating evidence indicates that some PTPs have an important role in the inhibition or control of growth, whereas some PTPs exert oncogenic functions. This Review discusses the relevance of PTPs to cancer biology and their potential as therapeutic targets.

Inherent difficulties with blocking many desirable targets using conventional approaches have prompted many to consider using RNA interference (RNAi) as a therapeutic approach. This Review explores current challenges to the development of synthetic RNAi-based therapies and considers new approaches to circumvent biological barriers.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease that often recurs, prompting the field cancerization hypothesis. This Review discusses the molecular pathology of HNSCC and how its heterogeneity can be used to classify the disease and provide a model of HNSCC development.

The Pim family of kinases actively collaborate with MYC in driving tumorigenesis. However, in several cancers the expression levels of PIMs can correlate with favourable prognostic outcome. This Review analyses the physiological and oncogenic activities of Pim kinases and their synergistic marriage with MYC, for better or for worse.

Genetic analyses of the normal development of the nematodeCaenorhabditis elegans have revealed evolutionarily conserved mechanisms through which individual cells establish their fates, and how they make and execute the decision to survive or undergo programmed cell death. Mammalian counterparts of these pathways are co-opted by malignant cells, and studies in C.elegansare helping to identify new anticancer drugs.

Adaptor (or scaffold) proteins form signalling platforms that regulate downstream signalling events. Evidence suggests that adaptors functioning downstream of integrins and receptor tyrosine kinases are deregulated in cancer and have important roles in mediating tumour cell survival, proliferation and motility.

Certain members of the Ras superfamily of small GTPases are commonly deregulated in human cancers, but how can we target them? This Review explores the association of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that regulate GTPases with cancer and discusses whether they can be effectively targeted therapeutically.

The polo-like kinases and aurora kinases have various roles in mitosis, and inhibitors of these kinases are being tested in clinical trials. Recent data have shown that extensive crosstalk exists between the polo-like kinase and aurora kinase pathways, which might affect the efficacy of these drugs. This Review discusses the biology of these kinases and how drugs that inhibit them might be used in the clinic.

EGFRmutations define a subset of lung cancers associated with sensitivity to the kinase inhibitors gefitinib and erlotinib. However, primary and acquired resistance remains a major clinical problem. This article reviews recent advances towards biologically based rational treatment of this disease.

This Review discusses the new data that have revealed surprising insights into the pathogenesis of acute promyelocytic leukaemia (APL) and the mechanism by which retinoic acid plus arsenic trioxide combination therapy targets the oncogenic fusion protein promyelocytic leukaemia (PML)–retinoic acid receptor-α (RARα), curing most cases of APL.

This Review describes the evidence linking the renin–angiotensin system (RAS) to cancer, through its roles in processes such as apoptosis, angiogenesis and tissue remodelling. Could RAS inhibitors currently used in the clinic be retooled to treat cancer?

Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of KS. This Review discusses the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 15 years.

Polycomb and trithorax group proteins have opposing effects on chromatin, and either repress or activate gene expression, respectively. Therefore, the dynamic interplay between these protein families has complex effects on epigenetic regulation and consequently tumour biology.

Transposon-based insertional mutagenesis (TIM) provides an alternative method for cancer gene discovery. This Review discusses how the mobilization of the transposon Tc1/mariner, Sleeping Beauty (SB), in mouse cells at frequencies high enough to induce cancer has facilitated the identification of the genes and signalling pathways that drive tumour formation.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by near-universal mutations in KRAS and frequent deregulation of the Hedgehog (Hh) and Wnt–β-catenin pathways. This Review examines the central part that KRAS plays in the biology of PDAC, and how the timing and location of Hh and Wnt–β-catenin signalling dictate the specification and oncogenic properties of PDAC.

Proteomics approaches are increasingly being used to functionally characterize proteins and signalling pathways, including the roles of complexes and post-translational modifications. This Review illustrates how these techniques have been used to find new aspects of receptor tyrosine kinase-mediated signal transduction pathways in cancer.

Antibody-based proteomics facilitates the high-throughput evaluation of candidate biomarkers. What insights can be gained, and what are the clinical applications of antibody-based proteomics?

This Review focuses on activity-based protein profiling, which enables the discovery of cancer-relevant enzymes and selective pharmacological probes to perturb and characterize these proteins in tumour cells. When ABPP is integrated with other large-scale profiling methods, it can provide insight into the metabolic and signalling pathways that support cancer pathogenesis and indicate new strategies for treatment.

The ANGPT–TIE2 pathway is important for angiogenesis, lymphangiogenesis and inflammation, and therefore has important roles in cancer. Given the context-dependent and opposing effects of the ANGPTs, how do we target this pathway?

Numerous oncoproteins depend on the molecular chaperone heat shock protein 90 (HSP90). However, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which the chaperone participates in both neoplastic and normal cellular physiology.