Highlights of This Issue

Tenkerian and colleagues address the cross-regulation between the mTOR and eIF2 kinase pathways and the importance of these mechanisms for cell survival. The key finding is that mTORC2 can repress PERK through the activation of Akt/PKB and phosphorylation of an inhibitory PERK site (Thr-799), which interferes with the activity of this eIF2 kinase. This mechanism provides new insight into the cross-talk between the mTOR and eIF2 kinase pathways and provides an explanation for why loss of TSC function can induce eIF2 phosphorylation. These ideas are important for the development of new treatment strategies for many cancers.

The development of agents that selectively potentiate radiation and chemotherapy in DNA repair-deficient cancers is an attractive direction for cancer therapy. Stachelek and colleagues describe a novel series of such compounds identified by a high-throughput synthetic lethality screen. The compounds contain an aryl sulfonamide motif and strongly sensitize BRCA2-deficient tumors to DNA-damaging therapy. By themselves, they also induce synthetic lethality in cancer cells deficient in DNA repair-related genes, including BRCA2 and PTEN. This new class of agents also offers the possibility of heightened treatment efficacy with reduced toxicity through synergism with other targeted agents, such as PARP inhibitors.

The importance of protein translation and the possibility of therapeutically targeting this process in cancer cells are often overlooked. In the study by Kardos and colleagues, the significance of targeting protein translation in cancer by disrupting the synthesis of the amino acid proline is demonstrated. The study shows that melanoma cells require high proline concentrations for survival and are sensitive to disruption of these levels. Targeting aldehyde dehydrogenase (ALDH18A1), a key point in proline biosynthesis pathways, can be used to retard melanoma tumor development by activating the ser/thr protein kinase GCN2 (general control nonderepressible 2), which phosphorylates eIF2 causing downregulation of protein synthesis.

Reduced expression of the translation initiation factor eIF3e has been observed in both breast and lung tumors. Previous study has suggested that reduced eIF3e expression in breast cancer cells causes epithelial-to-mesenchymal transition (EMT), an event that drives tumor metastasis. Desnoyers and colleagues demonstrate that reduced eIF3e expression also causes EMT in non-small cell lung cancer (NSCLC). This reduced eIF3e expression leads to overproduction of the TGFβ cytokine, which is known to potently induce EMT. Moreover, inhibition of TGFβ signaling in NSCLC cells with reduced eIF3e expression reverses EMT, highlighting the potential to use TGFβ inhibition as a therapeutic for NSCLC patients whose tumors display reduced eIF3e expression.