A5047199360- Melanoma and MAPK Pathways
- Protein Kinase Regulation and GTPase Signaling
- Cellular Mechanics and Interactions
- Cell death mechanisms and regulation
- Computational Drug Discovery Methods
- Cancer Mechanisms and Therapy
- Cytokine Signaling Pathways and Interactions
- Ubiquitin and proteasome pathways
- PI3K/AKT/mTOR signaling in cancer
- Monoclonal and Polyclonal Antibodies Research
- Mitochondrial Function and Pathology
- Graphene and Nanomaterials Applications
- Endoplasmic Reticulum Stress and Disease
- Mast cells and histamine
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Microtubule and mitosis dynamics
- Autophagy in Disease and Therapy
- Retinal Development and Disorders
- Mechanisms of cancer metastasis
- Signaling Pathways in Disease
- CRISPR and Genetic Engineering
- Click Chemistry and Applications
- RNA Interference and Gene Delivery
- Polyamine Metabolism and Applications
Babraham Institute
2006-2024
Since nuclear envelope breakdown occurs during mitosis in metazoan cells, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. However, repression of remains controversial and mechanistic detail limited the suggestion CDK1 phosphorylates VPS34. Here, we show initiation macroautophagy, measured by translocation ULK complex autophagic puncta, is repressed mitosis, even when mTORC1 inhibited. Indeed, inactive reflecting its failure localize lysosomes due...
The mechanistic target of rapamycin (mTOR) protein kinase coordinates responses to nutrients and growth factors is an anti-cancer drug target. To anticipate how cells will respond adapt chronic mTOR complex (mTORC)1 mTORC2 inhibition, we have generated SW620 colon cancer with acquired resistance the ATP-competitive inhibitor AZD8055 (SW620:8055R). inhibited mTORC1 signalling caused a switch from cap-dependent internal ribosome entry site (IRES)-dependent translation in parental cells. In...
Abstract BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X L expression biases pool towards MCL1. Consequently, or synthetic lethal with MCL1 inhibitor AZD5991, driving profound tumour cell death requires BAK/BAX, inhibiting growth vivo. Combination...
Abstract Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF V600E or KRAS G13D reinstate ERK1/2 signalling. Here we show that and MEKi are reversible following drug withdrawal. Cells with addicted maintain a precise level signalling is optimal for cell proliferation survival, tumour growth in vivo. Robust activation withdrawal drives p57 KIP2 -dependent G1 cycle arrest senescence expression NOXA death, selecting against those cells amplified . required loss...
ERK5, encoded by MAPK7, has been proposed to play a role in cell proliferation, thus attracting interest as cancer therapeutic target. While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK1/2 pathway, ERK5 is directly activated MEK5. It that and RAF proteins can also promote activation. Here we investigated interplay between RAS-RAF-MEK-ERK signaling studied tumor proliferation 2 disease-relevant models. We demonstrate although an inducible form CRAF (CRAF:ER*) activate...
Abstract Recently it has been found that General Control Non-derepressible 2 (GCN2) can be activated by an array of small molecule ATP-competitive inhibitors, including clinically relevant compounds such as Ponatinib, and specifically designed to GCN2 GCN2iB. Furthermore, we recently showed in cells approved RAF inhibitors. is a drug target, cancers mesothelioma, better understanding this paradoxical activation required develop drugs which truly inhibit the enzyme. Using biochemical assays...
Abstract Paradoxical RAF activation by chemical inhibitors (RAFi) is a well-understood ‘on-target’ biological and clinical response. In this study, we show that range of RAFi drive ERK1/2-independent the Unfolded Protein Response (UPR), including expression ATF4 CHOP, required translation initiation factor eIF2α. RAFi-induced CHOP was not reversed inhibition PERK, known upstream activator eIF2α-dependent Integrated Stress (ISR). Rather, found exposure activated GCN2, an alternate eIF2α...
The RAS–RAF–MEK–ERK pathway has been intensively studied in oncology, with RAS known to be mutated ∼30% of all human cancers. recent emergence ERK1/2 inhibitors and their ongoing clinical investigation demands a better understanding behavior following small-molecule inhibition. Although fluorescent fusion proteins antibodies are well-established methods visualizing proteins, we show that can visualized via less-invasive approach based on two-step process using inverse electron demand...
The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is activated in cancer due to mutations RAS proteins (especially KRAS), BRAF, CRAF, MEK1 and MEK2. Whilst inhibitors of KRASG12C (lung adenocarcinoma) BRAF MEK1/2 (melanoma colorectal cancer) are clinically approved, acquired resistance remains a problem. Consequently, the search for new proteins), inhibitor modalities regulators this pathway, which may be drug targets, continues increasingly involves cell-based screens with small...
BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-XL expression biases pool towards MCL1. Consequently, or synthetic lethal with MCL1 inhibitor AZD5991, driving profound tumour cell death requires BAK/BAX, inhibiting tumour growth vivo. Combination...