Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic

Targeting SHP2 phosphatase in breast cancer overcomes RTK-mediated resistance to PI3K inhibitors

BACKGROUND: PI3K signaling is frequently activated in breast cancer and is targeted by PI3K inhibitors. However, resistance of tumor cells to PI3K inhibition, often mediated by activated receptor tyrosine kinases, is commonly observed and reduces the potency of PI3K inhibitors. Therefore, new treatment strategies to overcome resistance to PI3K inhibitors are urgently needed to boost their efficacy. The phosphatase SHP2, which plays a crucial role in mediating signal transduction between receptor tyrosine kinases and both the PI3K and MAPK pathways, is a potential target for combination treatment. METHODS: We tested combinations of PI3K and SHP2 inhibitors in several experimental breast cancer models that are resistant to PI3K inhibition. Using cell culturing, biochemical and genetic approaches, we evaluated tumor cell proliferation and signaling output in cells treated with PI3K and SHP2 inhibitors. RESULTS: Combination treatment with PI3K and SHP2 inhibitors counteracted both acquired and intrinsic breast cancer cell resistance to PI3K inhibition that is mediated by activated receptor tyrosine kinases. Dual PI3K and SHP2 inhibition blocked proliferation and led to sustained inactivation of PI3K and MAPK signaling, where resistant cells rapidly re-activated these pathways upon PI3K inhibitor monotreatment. In addition, we demonstrate that overexpression of SHP2 induced resistance to PI3K inhibition, and that SHP2 was frequently activated during the development of PI3K inhibitor resistance after prolonged treatment of sensitive cells. CONCLUSIONS: Our results highlight the importance of SHP2 as a player in resistance to PI3K inhibitors. Combination treatment with PI3K and SHP2 inhibitors could pave the way for significant improvements in therapies for breast cancer

Shadowing in the nuclear photoabsorption above the resonance region

A model based on the hadronic fluctuations of the real photon is developed to describe the total photonucleon and photonuclear cross sections in the energy region above the nucleon resonances. The hadronic spectral function of the photon is derived including the finite width of vector-meson resonances and the quark-antiquark continuum. The shadowing effect is evaluated considering the effective interaction of the hadronic component with the bound nucleons within a Glauber-Gribov multiple scattering theory. The low energy onset of the shadowing effect is interpreted as a possible signature of a modification of the hadronic spectral function in the nuclear medium. A decrease of the $\rho$-meson mass in nuclei is suggested for a better explanation of the experimental data.Comment: 8 pages, 7 figure

Normalising jurisdictional heterotopias through place branding : the cases of Christiania and Metelkova

This paper explores the political dimensions of place branding as a path to normalisation for areas where a paradoxical relationship with the law exists, places that we coin “jurisdictional heterotopias” borrowing from Foucauldian literature. We posit that place branding plays a fundamental role in facilitating scale jumping in the otherwise vertically aligned legal space, a hierarchy designed to exclude spatial multiplicity from its premise. By examining the role of place branding in such areas, we endeavour to understand and appreciate the selective application of the law, the perpetuation of unregulated and illegal activity, as well as the place – specificity of legal practice. Ultimately, we argue that strong place branding associations permit the engulfment of this type of heterotopias in the “mainstream” leading to their normalisation; such a normalisation results not only in the acceptance of their uniqueness by the institutional elements, but also in the potential nullification of the liberties their communities advocate

Radical, Reformist, and Garden-Variety Neoliberal: Coming to Terms with Urban Agriculture’s Contradictions

For many activists and scholars, urban agriculture in the Global North has become synonymous with sustainable food systems, standing in opposition to the dominant industrial agri-food system. At the same time, critical social scientists increasingly argue that urban agriculture programmes, by filling the void left by the rolling back of the social safety net, underwrite neoliberalisation. I argue that such contradictions are central to urban agriculture. Drawing on existing literature and fieldwork in Oakland, CA, I explain how urban agriculture arises from a protective counter-movement, while at the same time entrenching the neoliberal organisation of contemporary urban political economies through its entanglement with multiple processes of neoliberalisation. By focusing on one function or the other, however, rather than understanding such contradictions as internal and inherent, we risk undermining urban agriculture\u27s transformative potential. Coming to terms with its internal contradictions can help activists, policy-makers and practitioners better position urban agriculture within coordinated efforts for structural change, one of many means to an end rather than an end unto itself