Targeting HER proteins in cancer therapy and the role of the non-target HER3

Members of the human epidermal growth factor receptor (HER) family have been of considerable interest in the cancer arena due to their potential to induce tumorigenesis when their signalling functions are deregulated. The constitutive activation of these proteins is seen in a number of different common cancer subtypes, and in particular EGFR and HER2 have become highly pursued targets for anti-cancer drug development. Clinical studies in a number of different cancers known to be driven by EGFR or HER2 show mixed results, and further mechanistic understanding of drug sensitivity and resistance is needed to realise the full potential of this treatment modality. Signalling in trans is a key feature of HER family signalling, and the activation of the PI3K/Akt pathway, so critically important in tumorigenesis, is driven predominantly through phosphorylation in trans of the kinase inactive member HER3. An increasing body of evidence shows that HER3 plays a critical role in EGFR- and HER2-driven tumours. In particular, HER3 lies upstream of a critically important tumorigenic signalling pathway with extensive ability for feedback and cross-talk signalling, and targeting approaches that fail to account for this important trans-target of EGFR and HER2 can be undermined by its resiliency and resourcefulness. Since HER3 is kinase inactive, it is not a direct target of kinase inhibitors and not presently an easily drugable target. This review presents the current evidence highlighting the role of HER3 in tumorigenesis and its role in mediating resistance to inhibitors of EGFR and HER2

The Importance of Conserving Biodiversity Outside of Protected Areas in Mediterranean Ecosystems

Mediterranean-type ecosystems constitute one of the rarest terrestrial biomes and yet they are extraordinarily biodiverse. Home to over 250 million people, the five regions where these ecosystems are found have climate and coastal conditions that make them highly desirable human habitats. The current conservation landscape does not reflect the mediterranean biome's rarity and its importance for plant endemism. Habitat conversion will clearly outpace expansion of formal protected-area networks, and conservationists must augment this traditional strategy with new approaches to sustain the mediterranean biota. Using regional scale datasets, we determine the area of land in each of the five regions that is protected, converted (e.g., to urban or industrial), impacted (e.g., intensive, cultivated agriculture), or lands that we consider to have conservation potential. The latter are natural and semi-natural lands that are unprotected (e.g., private range lands) but sustain numerous native species and associated habitats. Chile has the greatest proportion of its land (75%) in this category and California-Mexico the least (48%). To illustrate the potential for achieving mediterranean biodiversity conservation on these lands, we use species-area curves generated from ecoregion scale data on native plant species richness and vertebrate species richness. For example, if biodiversity could be sustained on even 25% of existing unprotected, natural and semi-natural lands, we estimate that the habitat of more than 6,000 species could be represented. This analysis suggests that if unprotected natural and semi-natural lands are managed in a manner that allows for persistence of native species, we can realize significant additional biodiversity gains. Lasting biodiversity protection at the scale needed requires unprecedented collaboration among stakeholders to promote conservation both inside and outside of traditional protected areas, including on lands where people live and work

Combined Inactivation of MYC and K-Ras Oncogenes Reverses Tumorigenesis in Lung Adenocarcinomas and Lymphomas

Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as "oncogene-addiction." However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment.To examine how the MYC and K-ras(G12D) oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-ras(G12D) to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-, K-ras(G12D)- or MYC/K-ras(G12D)-induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas K-ras(G12D)-induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-ras(G12D) resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-ras(G12D) in maintenance of lung tumors, we found that the down-stream mediators of K-ras(G12D) signaling, Stat3 and Stat5, are dephosphorylated following conditional K-ras(G12D) but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-ras(G12D). Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation.Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic pathways is more likely to be effective in the treatment of lung cancers and lymphomas

Semiautomated isolation and molecular characterisation of single or highly purified tumour cells from CellSearch enriched blood samples using dielectrophoretic cell sorting.

Molecular characterisation of single circulating tumour cells (CTCs) holds considerable promise for predictive biomarker assessment and to explore CTC heterogeneity. We evaluate a new method, the DEPArray system, that allows the dielectrophoretic manipulation and isolation of single and 100% purified groups of CTCs from pre-enriched blood samples and explore the feasibility of their molecular characterisation.info:eu-repo/semantics/publishe