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  • 1
    Language: English
    In: The Journal of cell biology, 2008-10-06, Vol.183 (1), p.101-116
    Description: Although Akt is known as a survival kinase, inhibitors of the phosphatidylinositol 3-kinase (PI3K)--Akt pathway do not always induce substantial apoptosis. We show that silencing Akt1 alone, or any combination of Akt isoforms, can suppress the growth of tumors established from phosphatase and tensin homologue--null human cancer cells. Although these findings indicate that Akt is essential for tumor maintenance, most tumors eventually rebound. Akt knockdown or inactivation with small molecule inhibitors did not induce significant apoptosis but rather markedly increased autophagy. Further treatment with the lysosomotropic agent chloroquine caused accumulation of abnormal auto-phagolysosomes and reactive oxygen species, leading to accelerated cell death in vitro and complete tumor remission in vivo. Cell death was also promoted when Akt inhibition was combined with the vacuolar H⁺--adenosine triphosphatase inhibitor bafilomycin A1 or with cathepsin inhibition. These results suggest that blocking lysosomal degradation can be detrimental to cancer cell survival when autophagy is activated, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PIK-Akt pathway inhibition.
    Subject(s): Adenosine triphosphatase ; Animals ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Apoptosis - physiology ; Autophagy - drug effects ; Autophagy - physiology ; Autophagy-Related Protein 7 ; Benzylamines - pharmacology ; Biochemistry ; Cancer ; Cell cycle ; Cell Cycle - drug effects ; Cell Cycle - genetics ; Cell Cycle - physiology ; Cell death ; Cell growth ; Cell Line, Tumor ; Cell lines ; Cell nucleus ; Cells ; Chloroquine - pharmacology ; Drug Interactions ; Female ; Fluorescence ; Furans - pharmacology ; Gene silencing ; Genetic aspects ; Humans ; Kinases ; Lysosomes - drug effects ; Lysosomes - metabolism ; Macrolides - pharmacology ; Mice ; Mice, Nude ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mutation ; Neoplasms - drug therapy ; Neoplasms - genetics ; Neoplasms - pathology ; Phosphatidylinositol ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Properties ; Protein isoforms ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Proton-Translocating ATPases - antagonists & inhibitors ; PTEN Phosphohydrolase - genetics ; Pyridines - pharmacology ; Pyrimidines - pharmacology ; Quinoxalines - pharmacology ; Reactive Oxygen Species - metabolism ; RNA Interference ; RNA, Small Interfering - genetics ; Tumors ; Ubiquitin-Activating Enzymes - genetics ; Xenograft Model Antitumor Assays
    ISSN: 0021-9525
    E-ISSN: 1540-8140
    Source: Rockefeller University Press
    Source: PubMed Central
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  • 2
    Language: English
    In: Science (American Association for the Advancement of Science), 2019-11-08, Vol.366 (6466), p.714-723
    Description: Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (Pl3K alpha) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased P13K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110 alpha binding to the inhibitory subunit p85 alpha, which relieves its catalytic inhibition, and increased p110 alpha membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3K alpha inhibitors compared with single-hotspot mutations.
    Subject(s): 1-Phosphatidylinositol 3-kinase ; Alleles ; Binding ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Carcinogenesis - genetics ; Cell Line, Tumor ; Cell proliferation ; Class I Phosphatidylinositol 3-Kinases - chemistry ; Class I Phosphatidylinositol 3-Kinases - genetics ; Class I Phosphatidylinositol 3-Kinases - metabolism ; Class Ia Phosphatidylinositol 3-Kinase - chemistry ; Class Ia Phosphatidylinositol 3-Kinase - metabolism ; Clinical trials ; Disruption ; Downstream effects ; Drug Resistance, Neoplasm - genetics ; Female ; Genomes ; Humans ; Inhibitors ; Kinases ; Lipids ; Multidisciplinary Sciences ; Mutation ; Neoplasms - drug therapy ; Neoplasms - genetics ; Neoplasms - pathology ; Phosphoinositide-3 Kinase Inhibitors - pharmacology ; Phosphoinositide-3 Kinase Inhibitors - therapeutic use ; Protein Binding ; Protein Domains ; Science & Technology ; Science & Technology - Other Topics ; Sensitivity analysis ; Signaling ; Thiazoles - pharmacology ; Tumors
    ISSN: 0036-8075
    E-ISSN: 1095-9203
    Source: Academic Search Ultimate
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 3
    Language: English
    In: Nature (London), 2010, Vol.464 (7287), p.431-435
    Description: Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects. Small molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.
    Subject(s): Adenosine Triphosphate - metabolism ; Animal tumors. Experimental tumors ; Animals ; Antineoplastic agents ; Benzamides - pharmacology ; Biological and medical sciences ; Cell Line ; Cell Membrane - drug effects ; Cell Membrane - metabolism ; Cell Proliferation - drug effects ; Cellular ; Cellular signal transduction ; Dimerization ; Diphenylamine - analogs & derivatives ; Diphenylamine - pharmacology ; Enzyme Activation - drug effects ; Experimental tumors, general aspects ; Extracellular Signal-Regulated MAP Kinases - metabolism ; General aspects ; Genetic aspects ; Growth ; Humans ; Indenes - pharmacology ; Indoles - pharmacology ; Inhibitors ; Kinases ; MAP Kinase Signaling System - drug effects ; Medical sciences ; Mice ; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors ; Mitogen-Activated Protein Kinase Kinases - metabolism ; Mitogen-activated protein kinases ; Neoplasms - drug therapy ; Neoplasms - enzymology ; Neoplasms - metabolism ; Neoplasms - pathology ; Pathways ; Pharmacology. Drug treatments ; Physiological aspects ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Transport - drug effects ; Proteins ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins B-raf - antagonists & inhibitors ; Proto-Oncogene Proteins B-raf - chemistry ; Proto-Oncogene Proteins B-raf - genetics ; Proto-Oncogene Proteins B-raf - metabolism ; Proto-Oncogene Proteins c-raf - deficiency ; Proto-Oncogene Proteins c-raf - genetics ; Proto-Oncogene Proteins c-raf - metabolism ; Proto-Oncogene Proteins p21(ras) ; Pyrazoles - pharmacology ; raf Kinases - antagonists & inhibitors ; raf Kinases - chemistry ; raf Kinases - genetics ; raf Kinases - metabolism ; Ras genes ; ras Proteins - genetics ; ras Proteins - metabolism ; Signalling ; Sulfonamides - pharmacology ; Tumors ; Tumours ; Xenograft Model Antitumor Assays
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Academic Search Ultimate
    Source: Get It Now
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  • 4
    Language: English
    In: Clinical cancer research, 2015-01-01, Vol.21 (1), p.77-86
    Description: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed 〉90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC 〉20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and 〉25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.
    Subject(s): Administration, Oral ; Adult ; Aged ; Dose-Response Relationship, Drug ; Drug-Related Side Effects and Adverse Reactions - pathology ; Female ; Humans ; Indazoles - administration & dosage ; Indazoles - blood ; Male ; Maximum Tolerated Dose ; Middle Aged ; Neoplasms - blood ; Neoplasms - drug therapy ; Neoplasms - genetics ; Neoplasms - pathology ; Phosphatidylinositol 3-Kinases - genetics ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - blood ; Protein Kinase Inhibitors - pharmacokinetics ; Proto-Oncogene Proteins B-raf - genetics ; Sulfonamides - administration & dosage ; Sulfonamides - blood
    ISSN: 1078-0432
    E-ISSN: 1557-3265
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 5
    Language: English
    In: Nature (London), 2013-09-12, Vol.501 (7466), p.232-236
    Description: KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients.
    Subject(s): Allosteric Regulation - drug effects ; Azetidines - pharmacology ; Cancer cells ; Cell Survival - drug effects ; Cellular control mechanisms ; Clinical Trials as Topic ; Crystallography, X-Ray ; Enzyme Activation - drug effects ; Feedback, Physiological - drug effects ; Gene mutations ; Genes, ras - genetics ; HCT116 Cells ; Humans ; Imidazoles - pharmacology ; MAP Kinase Signaling System - drug effects ; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors ; Mitogen-Activated Protein Kinase Kinases - chemistry ; Mitogen-Activated Protein Kinase Kinases - metabolism ; Mitogen-activated protein kinases ; Models, Molecular ; Neoplasms - enzymology ; Neoplasms - genetics ; Neoplasms - pathology ; Niacinamide - analogs & derivatives ; Niacinamide - pharmacology ; Oncogene Protein p21(ras) - genetics ; Phosphorylation - drug effects ; Phosphoserine - metabolism ; Phosphotransferases ; Physiological aspects ; Piperidines - pharmacology ; Properties ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins B-raf - genetics ; Proto-Oncogene Proteins B-raf - metabolism
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Academic Search Ultimate
    Source: Get It Now
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  • 6
    Language: English
    In: Clinical cancer research, 2009-07-15, Vol.15 (14), p.4649-4664
    Description: Purpose: The pathways underlying basal-like breast cancer are poorly understood, and as yet, there is no approved targeted therapy for this disease. We investigated the role of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors as targeted therapies for basal-like breast cancer. Experimental Design: We used pharmacogenomic analysis of a large panel of breast cancer cell lines with detailed accompanying molecular information to identify molecular predictors of response to a potent and selective inhibitor of MEK and also to define molecular mechanisms underlying combined MEK and PI3K targeting in basal-like breast cancer. Hypotheses were confirmed by testing in multiple tumor xenograft models. Results: We found that basal-like breast cancer models have an activated RAS-like transcriptional program and show greater sensitivity to a selective inhibitor of MEK compared with models representative of other breast cancer subtypes. We also showed that loss of PTEN is a negative predictor of response to MEK inhibition, that treatment with a selective MEK inhibitor caused up-regulation of PI3K pathway signaling, and that dual blockade of both PI3K and MEK/extracellular signal–regulated kinase signaling synergized to potently impair the growth of basal-like breast cancer models in vitro and in vivo . Conclusions: Our studies suggest that single-agent MEK inhibition is a promising therapeutic modality for basal-like breast cancers with intact PTEN, and also provide a basis for rational combination of MEK and PI3K inhibitors in basal-like cancers with both intact and deleted PTEN.
    Subject(s): Animals ; Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; basal-like breast cancer ; Biological and medical sciences ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Cluster Analysis ; combination therapy ; diagnostics ; Dose-Response Relationship, Drug ; EGFR ; Enzyme Inhibitors - pharmacology ; Female ; Flow Cytometry ; GDC-0941 ; Gene Expression Profiling ; Gynecology. Andrology. Obstetrics ; Humans ; Immunoblotting ; Mammary gland diseases ; Mammary Neoplasms, Experimental - drug therapy ; Mammary Neoplasms, Experimental - metabolism ; Mammary Neoplasms, Experimental - pathology ; MAP Kinase Kinase 1 - antagonists & inhibitors ; MAP Kinase Kinase 1 - genetics ; MAP Kinase Kinase 1 - metabolism ; Medical sciences ; MEK inhibitor ; Mice ; Mice, Inbred Strains ; Mice, Nude ; Mutation ; Oligonucleotide Array Sequence Analysis ; Pharmacology. Drug treatments ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; PI3K inhibitor ; PTEN ; PTEN Phosphohydrolase - genetics ; PTEN Phosphohydrolase - metabolism ; Tumors ; Xenograft Model Antitumor Assays
    ISSN: 1078-0432
    E-ISSN: 1557-3265
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 7
    Language: English
    In: Neoplasia (New York, N.Y.), 2014, Vol.16 (1), p.43-W19
    Description: Abstract Phosphoinositide 3-kinase (PI3K) pathway, in addition to its pro-proliferative and antiapoptotic effects on tumor cells, contributes to DNA damage repair (DDR). We hypothesized that GDC-0980, a dual PI3K-mammalian target of rapamycin (mTOR) inhibitor, would induce an efficient antitumor effect in BRCA-competent triple negative breast cancer (TNBC) model when combined with ABT888 and carboplatin. Mechanism-based in vitro studies demonstrated that GDC-0980 treatment alone or in combination led to DNA damage (increased pγH2AXS139 ; Western blot, immunofluorescence), gain in poly ADP-ribose (PAR), and a subsequent sensitization of BRCA-competent TNBC cells to ABT888 plus carboplatin with a time-dependent 1) decrease in proliferation signals (pAKTT308/S473 , pP70S6KT421/S424 , pS6RPS235/236 ), PAR/poly(ADP-ribose) polymerase (PARP) ratios, PAR/pγH2AX ratios, live/dead cell ratios, cell cycle progression, and three-dimensional clonogenic growths and 2) increase in apoptosis markers (cleaved caspases 3 and 9, a pro-apoptotic BH3-only of Bcl-2 family (BIM), cleaved PARP, annexin V). The combination was effective in vitro in BRCA-wild-type PIK3CA -H1047R-mutated BT20 and PTEN-null HCC70 cells. The combination blocked the growth of established xenograft tumors by 80% to 90% with a concomitant decrease in tumor Ki67, CD31, phosphorylated vascular endothelial growth factor receptor, pS6RPS235/236 , and p4EBP1T37/46 as well as an increase in cleaved caspase 3 immunohistochemistry (IHC) levels. Interestingly, a combination with GDC-0941, a pan-PI3K inhibitor, failed to block the tumor growth in MDA-MB231. Results demonstrate that the dual inhibition of PI3K and mTOR regulates DDR. In a BRCA-competent model, GDC-0980 enhanced the antitumor activity of ABT888 plus carboplatin by inhibiting both tumor cell proliferation and tumor-induced angiogenesis along with an increase in the tumor cell apoptosis. This is the first mechanism-based study to demonstrate the integral role of the PI3K-AKT-mTOR pathway in DDR-mediated antitumor action of PARP inhibitor in TNBC. Movie W1 Three-dimensional projection movie showing nuclear pyH2AXS139 foci in vehicle-treated MDA-MB468 cells at 24 hours. Movie W2 Three-dimensional projection movie showing the effect of GDC-0980 alone on nuclear pyH2AXS139 foci in MDA-MB468 cells at 24 hours Movie W3 Three-dimensional projection movie showing the absence of cytoplasmic cleaved caspase 3 in vehicle-treated MDA-MB468 cells at 72 hours. Movie W4 Three-dimensional projection movie showing abundance of cytoplasmic cleaved caspase 3 in GDC-0980 + ABT888 + carboplatin-treated MDA-MB468 cells at 72 hours.
    Subject(s): Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Benzimidazoles - pharmacology ; Carboplatin - pharmacology ; Caspase 3 - metabolism ; Cell Cycle - drug effects ; Cell Line, Tumor ; Cell Proliferation ; Drug Screening Assays, Antitumor ; Female ; Gene Expression Regulation, Neoplastic ; Genes, BRCA1 ; Genes, BRCA2 ; Humans ; Ki-67 Antigen - metabolism ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Oncology ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoproteins - metabolism ; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism ; Poly(ADP-ribose) Polymerase Inhibitors ; Proto-Oncogene Proteins c-akt - metabolism ; Ribosomal Protein S6 Kinases, 70-kDa - metabolism ; TOR Serine-Threonine Kinases - metabolism ; Triple Negative Breast Neoplasms - metabolism ; Vascular Endothelial Growth Factor A - metabolism
    ISSN: 1476-5586
    ISSN: 1522-8002
    E-ISSN: 1476-5586
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 8
    Language: English
    In: The Journal of experimental medicine, 2013-09-23, Vol.210 (10), p.1937-1945
    Description: Understanding the direct, tumor cell-intrinsic effects of PI 3-kinase (PI3K) has been a key focus of research to date. Here, we report that cancer cell-extrinsic PI3K activity, mediated by the p110α isoform of PI3K, contributes in an unexpected way to tumor angiogenesis. In syngeneic mouse models, inactivation of stromal p110α led to increased vascular density, reduced vessel size, and altered pericyte coverage. This increased vascularity lacked functionality, correlating with enhanced tumor hypoxia and necrosis, and reduced tumor growth. The role of p110α in tumor angiogenesis is multifactorial, and includes regulation of proliferation and DLL4 expression in endothelial cells. p110α in the tumor stroma is thus a regulator of vessel formation, with p110α inactivation giving rise to nonfunctional angiogenesis, which can stunt tumor growth. This type of vascular aberration differs from vascular endothelial growth factor-centered antiangiogenesis therapies, which mainly lead to vascular pruning. Inhibition of p110α may thus offer a new antiangiogenic therapeutic opportunity in cancer.
    Subject(s): Angiogènesi ; Animals ; Brief Definitive Report ; Cancer ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Class Ia Phosphatidylinositol 3-Kinase - antagonists & inhibitors ; Class Ia Phosphatidylinositol 3-Kinase - metabolism ; Càncer ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Enzyme Activation - drug effects ; Enzyme Inhibitors - pharmacology ; Humans ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Melanoma, Experimental ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Neoplasms - genetics ; Neoplasms - metabolism ; Neoplasms - pathology ; Neovascularization ; Neovascularization, Pathologic - genetics ; Neovascularization, Pathologic - metabolism ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - metabolism ; Stromal Cells - drug effects ; Stromal Cells - metabolism
    ISSN: 0022-1007
    E-ISSN: 1540-9538
    Source: Rockefeller University Press
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: PubMed Central
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  • 9
    Language: English
    In: The Journal of pathology, 2014-12, Vol.234 (4), p.502-513
    Description: Pancreatic adenocarcinoma (PDAC) is a major unmet medical need and a deeper understanding of molecular drivers is needed to advance therapeutic options for patients. We report here that p21‐activated kinase 1 (PAK1) is a central node in PDAC cells downstream of multiple growth factor signalling pathways, including hepatocyte growth factor (HGF) and MET receptor tyrosine kinase. PAK1 inhibition blocks signalling to cytoskeletal effectors and tumour cell motility driven by HGF/MET. MET antagonists, such as onartuzumab and crizotinib, are currently in clinical development. Given that even highly effective therapies have resistance mechanisms, we show that combination with PAK1 inhibition overcomes potential resistance mechanisms mediated either by activation of parallel growth factor pathways or by direct amplification of PAK1. Inhibition of PAK1 attenuated in vivo tumour growth and metastasis in a model of pancreatic adenocarcinoma. In human tissues, PAK1 is highly expressed in a proportion of PDACs (33% IHC score 2 or 3; n = 304) and its expression is significantly associated with MET positivity (p 〈 0.0001) and linked to a widespread metastatic pattern in patients (p = 0.067). Taken together, our results provide evidence for a functional role of MET/PAK1 signalling in pancreatic adenocarcinoma and support further characterization of therapeutic inhibitors in this indication. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
    Subject(s): Adenocarcinoma - metabolism ; Adenocarcinoma - pathology ; Analysis ; Animals ; Antibodies, Monoclonal - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Azetidines - pharmacology ; Cell Movement - drug effects ; Disease Models, Animal ; Drug Resistance, Neoplasm - physiology ; GDC-0941 (pictilisib) ; Humans ; Immunohistochemistry ; MET ; Metastasis ; Mice ; onartuzumab ; p21-Activated Kinases - metabolism ; PAK1 ; pancreatic adenocarcinoma ; Pancreatic cancer ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Piperidines - pharmacology ; Proto-Oncogene Proteins c-met - metabolism ; Signal Transduction - drug effects ; Signal Transduction - physiology
    ISSN: 0022-3417
    E-ISSN: 1096-9896
    Source: Hellenic Academic Libraries Link
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  • 10
    Language: English
    In: PloS one, 2012, Vol.7 (5), p.e36402-e36402
    Description: The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3) production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.
    Subject(s): 1-Phosphatidylinositol 3-kinase ; AKT protein ; Alleles ; Biology ; Breast cancer ; Cancer ; Cell culture ; Cell growth ; Cell Line, Tumor ; Cell Movement - genetics ; Cell Survival - genetics ; Chemical compounds ; Class I Phosphatidylinositol 3-Kinases ; Cluster Analysis ; Enzyme Activation - genetics ; Epithelial cells ; Epithelial-Mesenchymal Transition - genetics ; Gene expression ; Gene Expression Profiling ; Gene Silencing ; Genetic aspects ; Genotype & phenotype ; Health aspects ; Humans ; Indazoles - pharmacology ; Insulin ; Invasiveness ; Kinases ; Laboratories ; Medical research ; Medicine, Experimental ; Mesenchyme ; Metastases ; Metastasis ; Mutation ; Neoplasms - genetics ; Neoplasms - metabolism ; Oncology ; Penicillin ; Pharmacology ; Phenotype ; Phosphatidylinositol 3,4,5-triphosphate ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Positive feedback ; Protein Interaction Domains and Motifs - genetics ; PTEN protein ; Reversing ; RNA Interference ; Signal Transduction - drug effects ; Signaling ; Sulfonamides - pharmacology ; TOR protein
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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