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Results: 1 to 10 of 238

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Systems-level network modeling of Small Cell Lung Cancer subtypes identifies master regulators and destabilizers.
Wooten DJ, Groves SM, Tyson DR, Liu Q, Lim JS, Albert R, Lopez CF, Sage J, Quaranta V
(2019) PLoS Comput Biol 15: e1007343
MeSH Terms: Algorithms, Animals, Basic Helix-Loop-Helix Transcription Factors, Bayes Theorem, Cell Line, Tumor, Cluster Analysis, Databases, Genetic, Drug Resistance, Neoplasm, Gene Expression, Gene Expression Regulation, Neoplastic, Gene Ontology, Gene Regulatory Networks, Humans, Mice, Models, Theoretical, Small Cell Lung Carcinoma, Systems Analysis, Transcription Factors
Show Abstract · Added March 30, 2020
Adopting a systems approach, we devise a general workflow to define actionable subtypes in human cancers. Applied to small cell lung cancer (SCLC), the workflow identifies four subtypes based on global gene expression patterns and ontologies. Three correspond to known subtypes (SCLC-A, SCLC-N, and SCLC-Y), while the fourth is a previously undescribed ASCL1+ neuroendocrine variant (NEv2, or SCLC-A2). Tumor deconvolution with subtype gene signatures shows that all of the subtypes are detectable in varying proportions in human and mouse tumors. To understand how multiple stable subtypes can arise within a tumor, we infer a network of transcription factors and develop BooleaBayes, a minimally-constrained Boolean rule-fitting approach. In silico perturbations of the network identify master regulators and destabilizers of its attractors. Specific to NEv2, BooleaBayes predicts ELF3 and NR0B1 as master regulators of the subtype, and TCF3 as a master destabilizer. Since the four subtypes exhibit differential drug sensitivity, with NEv2 consistently least sensitive, these findings may lead to actionable therapeutic strategies that consider SCLC intratumoral heterogeneity. Our systems-level approach should generalize to other cancer types.
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Radiosensitization by enzalutamide for human prostate cancer is mediated through the DNA damage repair pathway.
Sekhar KR, Wang J, Freeman ML, Kirschner AN
(2019) PLoS One 14: e0214670
MeSH Terms: Aged, Animals, Cell Line, Tumor, Cell Proliferation, DNA Damage, DNA Repair, Drug Resistance, Neoplasm, Humans, Male, Mice, Mice, Nude, Mice, Transgenic, Phenylthiohydantoin, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Radiation Tolerance, Radiation-Sensitizing Agents, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second-generation anti-androgen with high affinity and activity that is used for the treatment of metastatic disease. Although radiosensitization mechanisms are known to be mediated through androgen receptor activity, this project aims to uncover the detailed DNA damage repair factors influenced by enzalutamide using multiple models of androgen-sensitive (LNCaP) and castration-resistant human prostate cancer (22Rv1 and DU145). Enzalutamide is able to radiosensitize both androgen-dependent and androgen-independent human prostate cancer models in cell culture and xenografts in mice, as well as a treatment-resistant patient-derived xenograft. The enzalutamide-mediated mechanism of radiosensitization includes delay of DNA repair through temporal prolongation of the repair factor complexes and halting the cell cycle, which results in decreased colony survival. Altogether, these findings support the use of enzalutamide concurrently with radiotherapy to enhance the treatment efficacy for prostate cancer.
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19 MeSH Terms
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
Repurposing cabozantinib to GISTs: Overcoming multiple imatinib-resistant cKIT mutations including gatekeeper and activation loop mutants in GISTs preclinical models.
Lu T, Chen C, Wang A, Jiang Z, Qi Z, Hu Z, Hu C, Liu F, Wang W, Wu H, Wang B, Wang L, Qi S, Wu J, Wang W, Tang J, Yan H, Bai M, Liu Q, Liu J
(2019) Cancer Lett 447: 105-114
MeSH Terms: Anilides, Antineoplastic Agents, Cell Line, Tumor, Drug Repositioning, Drug Resistance, Neoplasm, Gastrointestinal Stromal Tumors, Humans, Imatinib Mesylate, Mutation, Proto-Oncogene Proteins c-kit, Pyridines
Show Abstract · Added April 2, 2019
Despite of the great success of imatinib as the first-line treatment for GISTs, the majority of patients will develop drug-acquired resistance due to secondary mutations in the cKIT kinase. Sunitinib and regorafenib have been approved as the second and third line therapies to overcome some of these drug-resistance mutations; however, their limited clinical response, toxicity and resistance of the activation loop mutants still makes new therapies bearing different cKIT mutants activity spectrum profile highly demanded. Through a drug repositioning approach, we found that cabozantinib exhibited higher potency than imatinib against primary gain-of-function mutations of cKIT. Moreover, cabozantinib was able to overcome cKIT gatekeeper T670I mutation and the activation loop mutations that are resistant to imatinib or sunitinib. Cabozantinib demonstrated good efficacy in vitro and in vivo in the cKIT mutant-driven preclinical models of GISTs while displaying a long-lasting effect after treatment withdrawal. Furthermore, it also exhibited dose-dependent anti-proliferative efficacy in the GIST patient derived primary cells. Considering clinical safety and PK profile of cabozantinib, this report provides the basis for the future clinical applications of cabozantinib as an alternative anti-GISTs therapy in precision medicine.
Copyright © 2019 Elsevier B.V. All rights reserved.
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11 MeSH Terms
Insight on mutation-induced resistance to anaplastic lymphoma kinase inhibitor ceritinib from molecular dynamics simulations.
He MY, Li WK, Meiler J, Zheng QC, Zhang HX
(2019) Biopolymers 110: e23257
MeSH Terms: Adenosine Triphosphate, Anaplastic Lymphoma Kinase, Binding Sites, Drug Resistance, Neoplasm, Humans, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Neoplasms, Principal Component Analysis, Protein Kinase Inhibitors, Protein Structure, Tertiary, Pyrimidines, Sulfones
Show Abstract · Added March 21, 2020
Ceritinib, an advanced anaplastic lymphoma kinase (ALK) next-generation inhibitor, has been proved excellent antitumor activity in the treatment of ALK-associated cancers. However, the accumulation of acquired resistance mutations compromise the therapeutic efficacy of ceritinib. Despite abundant mutagenesis data, the structural determinants for reduced ceritinib binding in mutants remains elusive. Focusing on the G1123S and F1174C mutations, we applied molecular dynamics (MD) simulations to study possible reasons for drug resistance caused by these mutations. The MD simulations predict that the studied mutations allosterically impact the configurations of the ATP-binding pocket. An important hydrophobic cluster is identified that connects P-loop and the αC-helix, which has effects on stabilizing the conformation of ATP-binding pocket. It is suggested, in this study, that the G1123S and F1174C mutations can induce the conformational change of P-loop thereby causing the reduced ceritinib affinity and causing drug resistance.
© 2019 Wiley Periodicals, Inc.
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Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma.
Panda A, de Cubas AA, Stein M, Riedlinger G, Kra J, Mayer T, Smith CC, Vincent BG, Serody JS, Beckermann KE, Ganesan S, Bhanot G, Rathmell WK
(2018) JCI Insight 3:
MeSH Terms: Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, B7-H1 Antigen, Carcinoma, Renal Cell, Datasets as Topic, Drug Resistance, Neoplasm, Endogenous Retroviruses, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Male, Middle Aged, Programmed Cell Death 1 Receptor, Progression-Free Survival, Retrospective Studies, Sequence Analysis, RNA
Show Abstract · Added October 30, 2019
Although a subset of clear cell renal cell carcinoma (ccRCC) patients respond to immune checkpoint blockade (ICB), predictors of response remain uncertain. We investigated whether abnormal expression of endogenous retroviruses (ERVs) in tumors is associated with local immune checkpoint activation (ICA) and response to ICB. Twenty potentially immunogenic ERVs (πERVs) were identified in ccRCC in The Cancer Genome Atlas data set, and tumors were stratified into 3 groups based on their expression levels. πERV-high ccRCC tumors showed increased immune infiltration, checkpoint pathway upregulation, and higher CD8+ T cell fraction in infiltrating leukocytes compared with πERV-low ccRCC tumors. Similar results were observed in ER+/HER2- breast, colon, and head and neck squamous cell cancers. ERV expression correlated with expression of genes associated with histone methylation and chromatin regulation, and πERV-high ccRCC was enriched in BAP1 mutant tumors. ERV3-2 expression correlated with ICA in 11 solid cancers, including the 4 named above. In a small retrospective cohort of 24 metastatic ccRCC patients treated with single-agent PD-1/PD-L1 blockade, ERV3-2 expression in tumors was significantly higher in responders compared with nonresponders. Thus, abnormal expression of πERVs is associated with ICA in several solid cancers, including ccRCC, and ERV3-2 expression is associated with response to ICB in ccRCC.
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19 MeSH Terms
Genetic and Phenotypic Diversification of Heterogeneous Tumor Populations.
Elion DL, Cook RS
(2018) Trends Mol Med 24: 655-656
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Drug Resistance, Neoplasm, Humans, Neoadjuvant Therapy, Triple Negative Breast Neoplasms
Show Abstract · Added April 15, 2019
Chemotherapy is the most commonly prescribed treatment for patients with aggressive and lethal triple negative breast cancers (TNBCs), which often develop chemoresistance. A recent study combined single nucleus sequencing, single cell RNA sequencing, and evolutionary biology to understand how tumor cells use genetic and phenotypic diversity to evade the selective pressures of neoadjuvant chemotherapy.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers.
Peng X, Chen Z, Farshidfar F, Xu X, Lorenzi PL, Wang Y, Cheng F, Tan L, Mojumdar K, Du D, Ge Z, Li J, Thomas GV, Birsoy K, Liu L, Zhang H, Zhao Z, Marchand C, Weinstein JN, Cancer Genome Atlas Research Network, Bathe OF, Liang H
(2018) Cell Rep 23: 255-269.e4
MeSH Terms: Cell Line, Tumor, Core Binding Factor Alpha 2 Subunit, Drug Resistance, Neoplasm, HEK293 Cells, Humans, Metabolic Networks and Pathways, Neoplasms, Snail Family Transcription Factors, Transcriptome
Show Abstract · Added October 30, 2019
Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1-master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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A Nonquiescent "Idling" Population State in Drug-Treated, BRAF-Mutated Melanoma.
Paudel BB, Harris LA, Hardeman KN, Abugable AA, Hayford CE, Tyson DR, Quaranta V
(2018) Biophys J 114: 1499-1511
MeSH Terms: Cell Line, Tumor, Drug Resistance, Neoplasm, Epigenesis, Genetic, Humans, Melanoma, Molecular Targeted Therapy, Mutation, Proto-Oncogene Proteins B-raf
Show Abstract · Added April 15, 2018
Targeted therapy is an effective standard of care in BRAF-mutated malignant melanoma. However, the duration of tumor remission varies unpredictably among patients, and relapse is almost inevitable. Here, we examine the responses of several BRAF-mutated melanoma cell lines (including isogenic subclones) to BRAF inhibitors. We observe complex response dynamics across cell lines, with short-term responses (<100 h) varying from cell line to cell line. In the long term, however, we observe equilibration of all drug-treated populations into a nonquiescent state characterized by a balanced rate of death and division, which we term the "idling" state, and to our knowledge, this state has not been previously reported. Using mathematical modeling, we propose that the observed population-level dynamics are the result of cells transitioning between basins of attraction within a drug-modified phenotypic landscape. Each basin is associated with a drug-induced proliferation rate, a recently introduced metric of an antiproliferative drug effect. The idling population state represents a new dynamic equilibrium in which cells are distributed across the landscape such that the population achieves zero net growth. By fitting our model to experimental drug-response data, we infer the phenotypic landscapes of all considered melanoma cell lines and provide a unifying view of how BRAF-mutated melanomas respond to BRAF inhibition. We hypothesize that the residual disease observed in patients after targeted therapy is composed of a significant number of idling cells. Thus, defining molecular determinants of the phenotypic landscape that idling populations occupy may lead to "targeted landscaping" therapies based on rational modification of the landscape to favor basins with greater drug susceptibility.
Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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8 MeSH Terms
lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling.
Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, Singh B, Franklin JL, Wang J, Hu H, Wei T, Yang M, Yeatman TJ, Lee E, Saito-Diaz K, Hinger S, Patton JG, Chung CH, Emmrich S, Klusmann JH, Fan D, Coffey RJ
(2017) Nat Med 23: 1331-1341
MeSH Terms: Antineoplastic Agents, Immunological, Cell Line, Tumor, Cetuximab, Disease Progression, Drug Resistance, Neoplasm, Epigenesis, Genetic, GATA6 Transcription Factor, Humans, MicroRNAs, RNA, Long Noncoding, Signal Transduction, Wnt Proteins, beta Catenin
Show Abstract · Added April 3, 2018
De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor (EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance. MIR100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. Our results describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These findings identify a clinically actionable, epigenetic cause of cetuximab resistance.
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