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Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer.
Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA, Sudhan DR, Guerrero-Zotano AL, Croessmann S, Guo Y, Ericsson PG, Lee KM, Nixon MJ, Schwarz LJ, Sanders ME, Dugger TC, Cruz MR, Behdad A, Cristofanilli M, Bardia A, O'Shaughnessy J, Nagy RJ, Lanman RB, Solovieff N, He W, Miller M, Su F, Shyr Y, Mayer IA, Balko JM, Arteaga CL
(2019) Nat Commun 10: 1373
MeSH Terms: Aminopyridines, Animals, Antineoplastic Agents, Hormonal, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Circulating Tumor DNA, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Drug Resistance, Neoplasm, Female, Fulvestrant, High-Throughput Nucleotide Sequencing, Humans, MCF-7 Cells, Mice, Mutation, Naphthalenes, Piperazines, Progression-Free Survival, Proportional Hazards Models, Protein Kinase Inhibitors, Purines, Pyrazoles, Pyridines, Quinolines, Quinoxalines, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Estrogen, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.
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32 MeSH Terms
HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism.
Haase VH
(2017) Hemodial Int 21 Suppl 1: S110-S124
MeSH Terms: Anemia, Barbiturates, Clinical Trials as Topic, Erythropoiesis, Erythropoietin, Glycine, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Iron, Isoquinolines, Picolinic Acids, Prolyl-Hydroxylase Inhibitors, Renal Dialysis
Show Abstract · Added April 28, 2017
A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.
© 2017 International Society for Hemodialysis.
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13 MeSH Terms
An Acquired Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.
Hanker AB, Brewer MR, Sheehan JH, Koch JP, Sliwoski GR, Nagy R, Lanman R, Berger MF, Hyman DM, Solit DB, He J, Miller V, Cutler RE, Lalani AS, Cross D, Lovly CM, Meiler J, Arteaga CL
(2017) Cancer Discov 7: 575-585
MeSH Terms: Afatinib, Antineoplastic Agents, Breast Neoplasms, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Humans, Middle Aged, Mutation, Phenotype, Protein Kinase Inhibitors, Quinazolines, Quinolines, Receptor, ErbB-2
Show Abstract · Added April 8, 2017
We report a gatekeeper mutation in a patient with -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 but not HER2 In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2-induced signaling and cell growth. Acquisition of HER2 upon development of resistance to neratinib in a breast cancer with an initial activating mutation suggests is a driver mutation. HER2-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. We found an acquired gatekeeper mutation in a patient with -mutant breast cancer upon clinical progression on neratinib. We speculate that may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. .
©2017 American Association for Cancer Research.
1 Communities
2 Members
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14 MeSH Terms
BMP Antagonist Gremlin 2 Limits Inflammation After Myocardial Infarction.
Sanders LN, Schoenhard JA, Saleh MA, Mukherjee A, Ryzhov S, McMaster WG, Nolan K, Gumina RJ, Thompson TB, Magnuson MA, Harrison DG, Hatzopoulos AK
(2016) Circ Res 119: 434-49
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Cells, Cultured, Endothelial Cells, Female, Humans, Inflammation, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myocardial Infarction, Myocytes, Cardiac, Proteins, Pyrazoles, Quinolines
Show Abstract · Added July 5, 2016
RATIONALE - We have recently shown that the bone morphogenetic protein (BMP) antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. Our initial studies discovered that Grem2 is strongly induced in the adult heart after experimental myocardial infarction (MI). However, the function of Grem2 and BMP-signaling inhibitors after cardiac injury is currently unknown.
OBJECTIVE - To investigate the role of Grem2 during cardiac repair and assess its potential to improve ventricular function after injury.
METHODS AND RESULTS - Our data show that Grem2 is transiently induced after MI in peri-infarct area cardiomyocytes during the inflammatory phase of cardiac tissue repair. By engineering loss- (Grem2(-/-)) and gain- (TG(Grem2)) of-Grem2-function mice, we discovered that Grem2 controls the magnitude of the inflammatory response and limits infiltration of inflammatory cells in peri-infarct ventricular tissue, improving cardiac function. Excessive inflammation in Grem2(-/-) mice after MI was because of overactivation of canonical BMP signaling, as proven by the rescue of the inflammatory phenotype through administration of the canonical BMP inhibitor, DMH1. Furthermore, intraperitoneal administration of Grem2 protein in wild-type mice was sufficient to reduce inflammation after MI. Cellular analyses showed that BMP2 acts with TNFα to induce expression of proinflammatory proteins in endothelial cells and promote adhesion of leukocytes, whereas Grem2 specifically inhibits the BMP2 effect.
CONCLUSIONS - Our results indicate that Grem2 provides a molecular barrier that controls the magnitude and extent of inflammatory cell infiltration by suppressing canonical BMP signaling, thereby providing a novel mechanism for limiting the adverse effects of excessive inflammation after MI.
© 2016 American Heart Association, Inc.
2 Communities
1 Members
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18 MeSH Terms
Lipoxin Inhibits Fungal Uptake by Macrophages and Reduces the Severity of Acute Pulmonary Infection Caused by Paracoccidioides brasiliensis.
Ribeiro LR, Loures FV, de Araújo EF, Feriotti C, Costa TA, Serezani CH, Jancar S, Calich VL
(2015) Mediators Inflamm 2015: 852574
MeSH Terms: Acetates, Animals, Arachidonate 5-Lipoxygenase, Dinoprostone, Inflammation Mediators, Leukotriene Antagonists, Leukotriene C4, Lipoxins, Macrophages, Alveolar, Male, Mice, Mice, 129 Strain, Mice, Inbred A, Mice, Knockout, Paracoccidioides, Paracoccidioidomycosis, Quinolines, Receptors, Leukotriene, Receptors, Pattern Recognition
Show Abstract · Added May 4, 2017
Cysteinyl leukotrienes (CysLTs) and lipoxins (LXs) are lipid mediators that control inflammation, with the former inducing and the latter inhibiting this process. Because the role played by these mediators in paracoccidioidomycosis was not investigated, we aimed to characterize the role of CysLT in the pulmonary infection developed by resistant (A/J) and susceptible (B10.A) mice. 48 h after infection, elevated levels of pulmonary LTC4 and LXA4 were produced by both mouse strains, but higher levels were found in the lungs of susceptible mice. Blocking the CysLTs receptor by MTL reduced fungal loads in B10.A, but not in A/J mice. In susceptible mice, MLT treatment led to reduced influx of PMN leukocytes, increased recruitment of monocytes, predominant synthesis of anti-inflammatory cytokines, and augmented expression of 5- and 15-lipoxygenase mRNA, suggesting a prevalent LXA4 activity. In agreement, MTL-treated macrophages showed reduced fungal burdens associated with decreased ingestion of fungal cells. Furthermore, the addition of exogenous LX reduced, and the specific blockade of the LX receptor increased the fungal loads of B10.A macrophages. This study showed for the first time that inhibition of CysLTs signaling results in less severe pulmonary paracoccidioidomycosis that occurs in parallel with elevated LX activity and reduced infection of macrophages.
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19 MeSH Terms
Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2.
Felts AS, Rodriguez AL, Smith KA, Engers JL, Morrison RD, Byers FW, Blobaum AL, Locuson CW, Chang S, Venable DF, Niswender CM, Daniels JS, Conn PJ, Lindsley CW, Emmitte KA
(2015) J Med Chem 58: 9027-40
MeSH Terms: Animals, Central Nervous System, Drug Discovery, Mice, Protein Binding, Quinolines, Quinolones, Rats, Receptor, Muscarinic M1, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
Both orthosteric and allosteric antagonists of the group II metabotropic glutamate receptors (mGlus) have been used to establish a link between mGlu2/3 inhibition and a variety of CNS diseases and disorders. Though these tools typically have good selectivity for mGlu2/3 versus the remaining six members of the mGlu family, compounds that are selective for only one of the individual group II mGlus have proved elusive. Herein we report on the discovery of a potent and highly selective mGlu2 negative allosteric modulator 58 (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides. The concept for the design of this series centered on morphing a quinoline series recently disclosed in the patent literature into a chemotype previously used for the preparation of muscarinic acetylcholine receptor subtype 1 positive allosteric modulators. Compound 58 exhibits a favorable profile and will be a useful tool for understanding the biological implications of selective inhibition of mGlu2 in the CNS.
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1 Members
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11 MeSH Terms
Changes in BQCA Allosteric Modulation of [(3)H]NMS Binding to Human Cortex within Schizophrenia and by Divalent Cations.
Dean B, Hopper S, Conn PJ, Scarr E
(2016) Neuropsychopharmacology 41: 1620-8
MeSH Terms: Allosteric Regulation, Cations, Divalent, Cerebral Cortex, Female, Humans, Male, Middle Aged, N-Methylscopolamine, Pirenzepine, Quinolines, Receptor, Muscarinic M1, Receptors, Muscarinic, Schizophrenia
Show Abstract · Added February 18, 2016
Stimulation of the cortical muscarinic M1 receptor (CHRM1) is proposed as a treatment for schizophrenia, a hypothesis testable using CHRM1 allosteric modulators. Allosteric modulators have been shown to change the activity of CHRMs using cloned human CHRMs and CHRM knockout mice but not human CNS, a prerequisite for them working in humans. Here we show in vitro that BQCA, a positive allosteric CHRM1 modulator, brings about the expected change in affinity of the CHRM1 orthosteric site for acetylcholine in human cortex. Moreover, this effect of BQCA is reduced in the cortex of a subset of subjects with schizophrenia, separated into a discrete population because of a profound loss of cortical [(3)H]pirenzepine binding. Surprisingly, there was no change in [(3)H]NMS binding to the cortex from this subset or those with schizophrenia but without a marked loss of cortical CHRM1. Hence, we explored the nature of [(3)H]pirenzepine and [(3)H]NMS binding to human cortex and showed total [(3)H]pirenzepine and [(3)H]NMS binding was reduced by Zn(2+), acetylcholine displacement of [(3)H]NMS binding was enhanced by Mg(2+) and Zn(2+), acetylcholine displacement of [(3)H]pirenzepine was reduced by Mg(2+) and enhanced by Zn(2+), whereas BQCA effects on [(3)H]NMS, but not [(3)H]pirenzepine, binding was enhanced by Mg(2+) and Zn(2+). These data suggest the orthosteric and allosteric sites on CHRMs respond differently to divalent cations and the effects of allosteric modulation of the cortical CHRM1 is reduced in a subset of people with schizophrenia, a finding that may have ramifications for the use of CHRM1 allosteric modulators in the treatment of schizophrenia.
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13 MeSH Terms
Tyrosine Kinase Inhibitor-Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia.
Moslehi JJ, Deininger M
(2015) J Clin Oncol 33: 4210-8
MeSH Terms: Aniline Compounds, Antineoplastic Agents, Cardiovascular System, Clinical Trials as Topic, Dasatinib, Fusion Proteins, bcr-abl, Humans, Hypertension, Imatinib Mesylate, Imidazoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Molecular Targeted Therapy, Nitriles, Protein Kinase Inhibitors, Pyridazines, Pyrimidines, Quinolines
Show Abstract · Added March 6, 2016
For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying cardiovascular AEs, and elucidate discrepancies between the reporting of such AEs between oncology and cardiovascular trials. Whenever possible, we provide practical recommendations, but we concede that cause-directed interventions will require better mechanistic understanding. We suggest that chronic myeloid leukemia heralds a fundamental shift in oncology toward effective but mostly noncurative long-term therapies. Realizing the full potential of these treatments will require a proactive rational approach to minimize long-term cardiovascular and cardiometabolic toxicities.
© 2015 by American Society of Clinical Oncology.
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17 MeSH Terms
Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth.
Hover LD, Young CD, Bhola NE, Wilson AJ, Khabele D, Hong CC, Moses HL, Owens P
(2015) Cancer Lett 368: 79-87
MeSH Terms: Antineoplastic Agents, Bone Morphogenetic Protein Receptors, Bone Morphogenetic Proteins, Cell Proliferation, Cisplatin, Disease-Free Survival, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Ovarian Neoplasms, Pyrazoles, Quinolines, Signal Transduction, Spheroids, Cellular, Tumor Cells, Cultured
Show Abstract · Added August 4, 2015
The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFβ) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue. We also determined that ovarian cancer cell lines have active BMP signaling in a cell autonomous fashion. Inhibition of BMP signaling with a small molecule receptor kinase antagonist is effective at reducing ovarian tumor sphere growth. Furthermore, BMP inhibition can enhance sensitivity to Cisplatin treatment and regulates gene expression involved in platinum resistance in ovarian cancer. Overall, these studies suggest targeting the BMP pathway as a novel source to enhance chemo-sensitivity in ovarian cancer.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
2 Communities
4 Members
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16 MeSH Terms
DNA polymerases κ and ζ cooperatively perform mutagenic translesion synthesis of the C8-2'-deoxyguanosine adduct of the dietary mutagen IQ in human cells.
Bose A, Pande P, Jasti VP, Millsap AD, Hawkins EK, Rizzo CJ, Basu AK
(2015) Nucleic Acids Res 43: 8340-51
MeSH Terms: DNA, DNA Adducts, DNA-Directed DNA Polymerase, Deoxyguanosine, HEK293 Cells, Humans, Mutagens, Mutation Rate, Quinolines
Show Abstract · Added January 7, 2016
The roles of translesion synthesis (TLS) DNA polymerases in bypassing the C8-2'-deoxyguanosine adduct (dG-C8-IQ) formed by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a highly mutagenic and carcinogenic heterocyclic amine found in cooked meats, were investigated. Three plasmid vectors containing the dG-C8-IQ adduct at the G1-, G2- or G3-positions of the NarI site (5'-G1G2CG3CC-3') were replicated in HEK293T cells. Fifty percent of the progeny from the G3 construct were mutants, largely G→T, compared to 18% and 24% from the G1 and G2 constructs, respectively. Mutation frequency (MF) of dG-C8-IQ was reduced by 38-67% upon siRNA knockdown of pol κ, whereas it was increased by 10-24% in pol η knockdown cells. When pol κ and pol ζ were simultaneously knocked down, MF of the G1 and G3 constructs was reduced from 18% and 50%, respectively, to <3%, whereas it was reduced from 24% to <1% in the G2 construct. In vitro TLS using yeast pol ζ showed that it can extend G3*:A pair more efficiently than G3*:C pair, but it is inefficient at nucleotide incorporation opposite dG-C8-IQ. We conclude that pol κ and pol ζ cooperatively carry out the majority of the error-prone TLS of dG-C8-IQ, whereas pol η is involved primarily in its error-free bypass.
© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
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9 MeSH Terms