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Current KRAS G12C (OFF) inhibitors that target inactive GDP-bound KRAS G12C cause responses in less than half of patients and these responses are not durable. A class of RAS G12C (ON) inhibitors that targets active GTP-bound KRAS G12C blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRAS G12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRAS G12C inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRAS G12C -dependent lung cancer. Despite the development of inhibitors targeting active GTP-bound (ON) KRAS(G12C) for the treatment of KRAS G12C-driven non-small cell lung cancer (NSCLC), resistance remains an issue. Here, the authors show that despite inhibition of KRAS G12C ON, there is residual mTOR activity driving resistance, which was successfully targeted by combining with a selective mTOR inhibitor.

Immunity to fungal infections is mediated by cells of the innate and adaptive immune system including Th17 cells. Ca 2+ influx in immune cells is regulated by stromal interaction molecule 1 (STIM1) and its activation of the Ca 2+ channel ORAI1. We here identify patients with a novel mutation in STIM1 (p.L374P) that abolished Ca 2+ influx and resulted in increased susceptibility to fungal and other infections. In mice, deletion of STIM1 in all immune cells enhanced susceptibility to mucosal C. albicans infection, whereas T cell‐specific deletion of STIM1 impaired immunity to systemic C. albicans infection. STIM1 deletion impaired the production of Th17 cytokines essential for antifungal immunity and compromised the expression of genes in several metabolic pathways including Foxo and HIF1α signaling that regulate glycolysis and oxidative phosphorylation (OXPHOS). Our study further revealed distinct roles of STIM1 in regulating transcription and metabolic programs in non‐pathogenic Th17 cells compared to pathogenic, proinflammatory Th17 cells, a finding that may potentially be exploited for the treatment of Th17 cell‐mediated inflammatory diseases. Synopsis Pathogenic Th17 cells have been implicated in autoimmune diseases, while non‐pathogenic Th17 cells provide immunity to fungal pathogens. Patients with mutations in ORAI1 or STIM1 have impaired Ca 2+ signaling in immune cells and are more susceptible to infections with fungal pathogens. A novel missense mutation in STIM1 (p.L374P) abolishes Ca 2+ signals in immune cells by interfering with the activation of ORAI1, the pore‐forming subunit of the calcium release‐activated calcium (CRAC) channel. T cells of patients with STIM1 p.L374P mutation fail to produce cytokines when challenged with C. albicans and have severe defects in metabolic functions including glycolysis and oxidative phosphorylation (OXPHOS). Deletion of STIM1 and its homologue STIM2 in all immune cells results in enhanced severity of mucosal C. albicans infection, which is associated with defective T cell and neutrophil function. T cell‐specific deletion of STIM1 reduces resistance to systemic C. albicans infection and is associated with impaired effector functions of Th1 and non‐pathogenic Th17 cells. STIM1 is required for the transcriptional regulation of aerobic glycolysis and OXPHOS in non‐pathogenic Th17 cells, whereas glycolysis in pathogenic Th17 cells is independent of STIM1 and CRAC channel function. Graphical Abstract Pathogenic Th17 cells have been implicated in autoimmune diseases, while non‐pathogenic Th17 cells provide immunity to fungal pathogens. Patients with mutations in ORAI1 or STIM1 have impaired Ca 2+ signaling in immune cells and are more susceptible to infections with fungal pathogens.

Current KRAS (OFF) inhibitors that target inactive GDP-bound KRAS cause responses in less than half of patients and these responses are not durable. A class of RAS (ON) inhibitors that targets active GTP-bound KRAS blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRAS inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRAS inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRAS -dependent lung cancer.

Background: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to overactive intrinsic mechanisms that mediate drug resistance. In addition, presence of mutant P53 further imparts resistance to conventional chemotherapeutic agents. Rigosertib, an investigational anticancer agent, target multiple kinases (CDK1, PLK1, VEGFR, and PDGFR) associated with oncogenic transformation and drug resistance. We have previously studied the inhibitory effect of Rigosertib with platinum based anticancer agents in various pre-clinical cancer models. Since Cisplatin (CDDP) is frequently used for treatment of UGC we investigated the potential therapeutic benefit of Rigosertib alone and in combination with CDDP by using both P53 wild type and mutant models of UGCs. Methods: For this study, we evaluated the effect of Rigosertib treatment alone and/or in combination with Cisplatin (CDDP) on AGS (P53 wild type) and FLO-1 (P53 mutant) UGC cell viability, survival, expression of apoptotic markers and late stage apoptosis. The MTT cell viability assay and Compusyn mediated median effect plot analysis (MEPA) (Chou and Talaly) were used to determine synergistic drug combinations of Rigosertib and CDDP in AGS and FLO-1 UGC cells, respectively. Results: The cell viability data and Compusyn generated MEPA indicated that Rigosertib and CDDP show synergistic anticancer activity in both AGS and FLO-1 UGC cells at a ratio of 1:10, respectively. Subsequent cell viability assays with Rigosertib and CDDP were done to establish the drug combinations that exhibited synergistic effect in AGS (Rigosertib:CDDP → 0.1 μM : 1,w1/1) and FLO-1 (Rigosertib:CDDP → 0.05 μM : 0.5μM) cells. The clonogenic cell survival assay data showed that in comparison to treatment with Rigosertib (AGS: 0.1μM; FLO-1: 0.05,μM) or CDDP (AGS: 1μM; FLO-1: 0.5,μM) alone; the combination treatment with Rigosertib and CDDP ((AGS: Rigo-0.1,μM and CDDP-1 μM; FLO-1 Rigo-0.05,μM and CDDP0.5,μM) significantly increased (p<0.05) inhibition of cellular survival in AGS and FLO-1 UGC cell lines. Similarly, the western blot data after treatment with Rigosertib (0.1µM) and/or CDDP (1 µM) for 24h induced higher levels of P53/P73, P21, Cleaved PARP and Cleaved Caspase 3 with Rigosertib (0.1µM) and CDDP (1µM) combination treatment in UGC cells. Lastly, Rigosertib and CDDP combination treatment for 24h significantly enhanced DNA fragmentation in UGC cells. Conclusions: Our in vitro data indicate that inhibition of various oncogenic kinases with Rigosertib is an effective therapeutic strategy for inducing apoptosis in P53 wild type and mutant UGC cells. Additionally, Rigosertib in combination with CDDP synergistically enhances the anti-tumor activity of CDDP against UGC cells. Therefore, our study suggests that Rigosertib is an effective anti-tumor agent which can be potentially combined with CDDP for better therapeutic outcome in patients suffering from UGC.

Insulin resistance is a condition associated with obesity, type 2 diabetes(T2D), hyperinsulinemia, hyperglycemia and defined by reduced sensitivity to insulin signaling. Molecular causes and early signaling events underlying insulin resistance are not well understood. Here we show that insulin activation of PI3K/AKT/mTOR signaling in insulin target tissues, causes mTORC1 induction of PTEN translation, a negative regulator of PI3K signaling. We hypothesized that insulin resistance is due to insulin dependent induction of PTEN that prevents further increases in PI3K signaling. In a diet induced animal model of obesity and insulin resistance, we show that PTEN levels are increased in fat, muscle, and liver. Hyperinsulinemia and PTEN induction are followed by hyperglycemia, severe glucose intolerance, and hepatic steatosis. In response to chronic hyperinsulinemia, PTEN remains increased, while AKT activity is induced transiently before settling down to a PTEN-high and AKT-low state in the tissues, predicted by computational modeling of the PTEN-AKT feedback loop. Treatment with PTEN and mTORC1 inhibitors prevent and reverse the effect of PTEN induction, rescue insulin resistance and increase PI3K/AKT signaling. Thus, we show that PTEN induction by increased insulin levels elevates feedback inhibition of the pathway causing insulin resistance, its associated phenotypes, and is a potential therapeutic target.

mutation occurs in 46% of melanomas and drives high levels of ERK activity and ERK-dependent proliferation. However, is insufficient to drive melanoma in GEMM models, and 82% of human benign nevi harbor mutations. We show here that BRAF inhibits mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induces RAC1 activation and restores migration and invasion. In cells with , mutant RAC1, overexpression of PREX1, PREX2, or PTEN inactivation restore RAC1 activity and cell motility. Together, these lesions occur in 48% of BRAF melanomas. Thus, although BRAF activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of cell migration. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers.

BRAFV600E mutation occurs in 46% of melanomas and drives high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600E is insufficient to drive melanoma in GEMM models, and 82% of human benign nevi harbor BRAFV600E mutations. We show here that BRAFV600E inhibits mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induces RAC1 activation and restores migration and invasion. In cells with BRAFV600E, mutant RAC1, overexpression of PREX1, PREX2, or PTEN inactivation restore RAC1 activity and cell motility. Together, these lesions occur in 48% of BRAFV600E melanomas. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of cell migration. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers.BRAFV600E mutation occurs in 46% of melanomas and drives high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600E is insufficient to drive melanoma in GEMM models, and 82% of human benign nevi harbor BRAFV600E mutations. We show here that BRAFV600E inhibits mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induces RAC1 activation and restores migration and invasion. In cells with BRAFV600E, mutant RAC1, overexpression of PREX1, PREX2, or PTEN inactivation restore RAC1 activity and cell motility. Together, these lesions occur in 48% of BRAFV600E melanomas. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of cell migration. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers.

Most cancer types lack effective targeted therapeutic options and in cancers where first-line targeted therapies are available, treatment resistance is a huge challenge. Recent technological advances enable the use of ATAC-seq and RNA-seq on patient biopsies in a high-throughput manner. Here we present a computational approach that leverages these datasets to identify novel drug targets based on tumor lineage. We constructed patient-specific gene regulatory networks for 371 patients of 22 cancer types using machine learning approaches trained using three-dimensional genomic data for enhancer to promoter contacts. Next, we identify the key transcription factors (TFs) in these networks, which are used to identify therapeutic vulnerabilities either by direct targeting of TFs or proteins that they co-operate with. We validate four novel candidates identified for neuroendocrine, liver and renal cancers, which have a dismal prognosis with current therapeutic options. We present a novel approach to use the increasing amounts of functional genomics data from patient biospecimens for identification of novel drug targets.

BRAFV600E mutation occurs in 46% of melanomas and drives high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600E is insufficient to drive melanoma in GEMM models, and 82% of human benign nevi harbor BRAFV600E mutations. We show here that BRAFV600E inhibits mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition leads to RAC1 activation and restores migration and invasion. In cells with BRAFV600E, activating RAC1 mutation, overexpression of PREX1, PREX2, or PTEN inactivation restore RAC1 activity and cell motility. Together, these lesions occur in 48% of BRAFV600E melanomas. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of cell migration. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers.Competing Interest StatementThe authors have declared no competing interest.

When polymer composites containing magnetic nanoparticles (MNPs) are exposed to an alternating magnetic field, heat is generated to melt the surrounding polymer locally, partially filling voids across any cracks or deformities. Such materials are of interest for structural applications; however, structural polymers with high melting temperatures pose the challenge of generating high localised temperatures enabling self-healing. A method to prepare a multiferroic-Polyamide 6 (PA6) nanocomposite with tuneable magnetocaloric properties is reported. Tunability arises from varying the MNP material (and any coating, its dispersion, and agglomerate sizes in the nanocomposite). The superparamagnetic MNPs (SMNPs) and iron oxide MNPs with and without surface functionalization were dispersed into PA6 through in situ polymerization, and their magnetic properties were compared. Furthermore, computer simulations were used to quantify the dispersion state of MNPs and assess the influence of the interaction radius on the magnetic response of the self-healable magnetic nanoparticle polymer (SHMNP) composite. It was shown that maintaining the low interaction radius through the dispersion of the low coercivity MNPs could allow tuning of the bulk magnetocaloric properties of the resulting mesostructures. An in-situ polymerization method improved the dispersion and reduced the maximum interaction radius value from ca. 806 to 371 nm and increased the magnetic response for the silica-coated SMNP composite. This sample displayed ca. three orders of magnitude enhancement for magnetic saturation compared to the unfunctionalized Fe 3 O 4 MNP composite.