Targeted therapy

mTOR inhibiton induces upstream receptor tyrosine kinase signaling and activates Akt. O'Reilly, K. E. et al. Cancer Res. 66, 1500–1508 (2006)

Stimulation of insulin-like growth factor 1 (IGF1) receptor induces the phosphatidylinositol 3-kinase (PI3K)–AKT–mTOR pathway, which is frequently activated in cancer cells. mTOR inhibition can arrest tumours in model systems, but shows limited anti-tumour activity in patients. O'Reilly et al. show that mTOR inhibition induces the expression of insulin receptor substrate 1, which, in turn, induces IGF1 receptor activity. This upregulates AKT and negates the effect of mTOR inhibition. This feedback mechanism might explain the poor therapeutic effect of mTOR inhibitors. Furthermore, IGF1 receptor inhibition is shown to sensitize cells to mTOR inhibition, indicating promise for future combination therapies.

Metastasis

Role of β-arrestin 1 in the metastatic progression of colorectal cancer. Buchanan, F. G. et al. Proc. Natl Acad. Sci. USA 103, 1492–1497 (2006)

The transactivation of growth factor receptors by ligand-activated G-protein-coupled receptors (GPCRs) has been implicated in human cancer-cell survival, proliferation and migration. Now, Raymond DuBois and colleagues show that β-arrestin is involved in the SRC-dependent pathway through which this transactivation occurs. The association of a ligand-activated GPCR–β-arrestin-1–SRC signalling complex results in transactivation of the epidermal-growth-factor receptor (EGFR) and downstream AKT signalling. Furthermore, the β-arrestin-1–SRC interaction is required for both colorectal carcinoma cell migration in vitro and metastatic spread of the disease in vivo.

Immunology

Autoimmunity and tumour immunity induced by immune responses to mutations in self. Engelhorn, M. E. et al. Nature Med. 29 Jan 2006 (10.1038/nm1363)

Weakly immunogenic tumours can be converted to strongly immunogenic ones by exposure to mutagens, and mutagenized tumours can induce immunity against the original tumour in mouse models. The basis for this is unclear, but work from Alan Houghton and colleagues indicates that specific mutations can alter the intracellular trafficking routes of proteins. This means that the mutant proteins are more likely to be presented as antigens rather than recognized as self peptides.

Chromosomal translocations

H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Franco, S. et al. Mol. Cell 21 201–214 (2006)

This paper shows that histone H2AX, a protein involved in the repair of DNA double-strand breaks, is an essential component for inhibiting chromosomal translocations that involve the immunoglobulin-heavy-chain locus (IgH) in activated B cells. Importantly, the authors conclude that mutation of the tumour suppressor and DNA-damage-response protein p53 does not influence the frequency of such IgH translocations, but instead might enable the expansion of B cells that harbour them.