An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

Seasonal predictability of the East Atlantic pattern from sea surface temperatures.

This study analyzes the influence of sea surface temperatures (SSTs) on the second mode of atmospheric variability in the north Atlantic/European sector, namely the East-Atlantic (EA) pattern, for the period 1950-2012. For this purpose, lead-lag relationships between SSTs and the EA pattern, ranging from 0 to 3 seasons, were assessed. As a main result, anomalies of the EA pattern in boreal summer and autumn are significantly related to SST anomalies in the Indo-Pacific Ocean during the preceding seasons. A statistical forecasting scheme based on multiple linear regression was used to hindcast the EA-anomalies with a lead-time of 1 to 2 months. The results of a one-year-out cross-validation approach indicate that the phases of the EA in summer and autumn can be properly hindcast.

Polyclonal hyper-IgE mouse model reveals mechanistic insights into antibody class switch recombination.

Preceding antibody constant regions are switch (S) regions varying in length and repeat density that are targets of activation-induced cytidine deaminase. We asked how participating S regions influence each other to orchestrate rearrangements at the IgH locus by engineering mice in which the weakest S region, Sε, is replaced with prominent recombination hotspot Sµ. These mice produce copious polyclonal IgE upon challenge, providing a platform to study IgE biology and therapeutic interventions. The insertion enhances ε germ-line transcript levels, shows a preference for direct vs. sequential switching, and reduces intraswitch recombination events at native Sµ. These results suggest that the sufficiency of Sµ to mediate IgH rearrangements may be influenced by context-dependent cues.

Critical role of activation induced cytidine deaminase in experimental autoimmune encephalomyelitis.

Multiple Sclerosis (MS) is a neurodegenerative autoimmune disorder caused by chronic inflammation and demyelination within the central nervous system (CNS). Clinical studies in MS patients have demonstrated efficacy with B cell targeted therapies such as anti-CD20. However, the exact role that B cells play in the disease process is unclear. Activation Induced cytidine deaminase (AID) is an essential enzyme for the processes of antibody affinity maturation and isotype switching. To evaluate the impact of affinity maturation and isotype switching, we have interrogated the effect of AID-deficiency in an animal model of MS. Here, we show that the severity of experimental autoimmune encephalomyelitis (EAE) induced by the extracellular domain of human myelin oligodendrocyte glycoprotein (MOG1-125) is significantly reduced in Aicda deficient mice, which, unlike wild-type mice, lack serum IgG to myelin associated antigens. MOG specific T cell responses are comparable between wild-type and Aicda knockout mice suggesting an active role for antigen experienced B cells. Thus affinity maturation and/or class switching are critical processes in the pathogenesis of EAE.

Disruption of PH-kinase domain interactions leads to oncogenic activation of AKT in human cancers.

The protein kinase v-akt murine thymoma viral oncogene homolog (AKT), a key regulator of cell survival and proliferation, is frequently hyperactivated in human cancers. Intramolecular pleckstrin homology (PH) domain-kinase domain (KD) interactions are important in maintaining AKT in an inactive state. AKT activation proceeds after a conformational change that dislodges the PH from the KD. To understand these autoinhibitory interactions, we generated mutations at the PH-KD interface and found that most of them lead to constitutive activation of AKT. Such mutations are likely another mechanism by which activation may occur in human cancers and other diseases. In support of this likelihood, we found somatic mutations in AKT1 at the PH-KD interface that have not been previously described in human cancers. Furthermore, we show that the AKT1 somatic mutants are constitutively active, leading to oncogenic signaling. Additionally, our studies show that the AKT1 mutants are not effectively inhibited by allosteric AKT inhibitors, consistent with the requirement for an intact PH-KD interface for allosteric inhibition. These results have important implications for therapeutic intervention in patients with AKT mutations at the PH-KD interface.

Changes in present and future circulation types frequency in northwest Iberian Peninsula.

The aim of the work described herein was to study projection scenarios in order to find changes in the synoptic variability of the northwest Iberian Peninsula in the 21st century. To this end, we investigated the changes in the frequency of the different circulation types computed for the study area using three different models used in the IPCC 4(th) assessment report. The circulation types were computed using the procedure known as Lamb circulation types. The control simulation for the late 20th century was evaluated objectively from the results obtained using data from the NCEP/NCAR reanalysis, as to evaluate the ability of the model to reproduce the present climate. We have compared not only seasonal mean sea level pressure fields but also the mean seasonal frequency of circulation types. The results for the end of the 21st century show a decrease in the frequency of cyclonic, W, and SW circulation types in the spring and summer months. This trend also appears in the autumn, with a concomitant increase in the anticyclonic types.

Increased targeting of donor switch region and IgE in Sgamma1-deficient B cells.

Ab class switch recombination involves a recombination between two repetitive DNA sequences known as switch (S) regions that vary in length, content, and density of the repeats. Abs expressed by B cells are diversified by somatic hypermutation and class switch recombination. Both class switch recombination and somatic hypermutation are initiated by activation-induced cytidine deaminase (AID), which preferentially recognizes certain hot spots that are far more enriched in the S regions. We found that removal of the largest S region, Sgamma1 (10 kb), in mice can result in the accumulation of mutations and short-range intra-S recombination in the donor Smu region. Furthermore, elevated levels of IgE were detected in trinitrophenol-OVA-immunized mice and in anti-CD40 plus IL-4-stimulated B cells in vitro. We propose that AID availability and targeting in part might be regulated by its DNA substrate. Thus, prominently transcribed S regions, such as Sgamma1, might provide a sufficient sink for AID protein to titrate away AID from other accessible sites within or outside the Ig locus.

DNA targets of AID evolutionary link between antibody somatic hypermutation and class switch recombination.

As part of the adaptive immune response, B cells alter their functional immunoglobulin (Ig) receptor genes through somatic hypermutation (SHM) and/or class switch recombination (CSR) via processes that are initiated by activation induced cytidine deaminase (AID). These genetic modifications are targeted at specific sequences known as Variable (V) and Switch (S) regions. Here, we analyze and review the properties and function of AID target sequences across species and compare them with non-Ig sequences, including known translocation hotspots. We describe properties of the S sequences, and discuss species and isotypic differences among S regions. Common properties of SHM and CSR target sequences suggest that evolution of S regions might involve the duplication and selection of SHM hotspots.