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miR-302a Inhibits Metastasis and Cetuximab Resistance in Colorectal Cancer by Targeting NFIB and CD44.
Sun L, Fang Y, Wang X, Han Y, Du F, Li C, Hu H, Liu H, Liu Q, Wang J, Liang J, Chen P, Yang H, Nie Y, Wu K, Fan D, Coffey RJ, Lu Y, Zhao X, Wang X
(2019) Theranostics 9: 8409-8425
MeSH Terms: Caco-2 Cells, Cetuximab, Colorectal Neoplasms, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Hyaluronan Receptors, In Vitro Techniques, MicroRNAs, NFI Transcription Factors, Neoplasm Metastasis, Signal Transduction
Show Abstract · Added March 3, 2020
: Metastasis and drug resistance contribute substantially to the poor prognosis of colorectal cancer (CRC) patients. However, the epigenetic regulatory mechanisms by which CRC develops metastatic and drug-resistant characteristics remain unclear. This study aimed to investigate the role of miR-302a in the metastasis and molecular-targeted drug resistance of CRC and elucidate the underlying molecular mechanisms. : miR-302a expression in CRC cell lines and patient tissue microarrays was analyzed by qPCR and fluorescence hybridization. The roles of miR-302a in metastasis and cetuximab (CTX) resistance were evaluated both and . Bioinformatic prediction algorithms and luciferase reporter assays were performed to identify the miR-302a binding regions in the NFIB and CD44 3'-UTRs. A chromatin immunoprecipitation assay was performed to examine NFIB occupancy in the ITGA6 promoter region. Immunoblotting was performed to identify the EGFR-mediated pathways altered by miR-302a. : miR-302a expression was frequently reduced in CRC cells and tissues, especially in CTX-resistant cells and patient-derived xenografts. The decreased miR-302a levels correlated with poor overall CRC patient survival. miR-302a overexpression inhibited metastasis and restored CTX responsiveness in CRC cells, whereas miR-302a silencing exerted the opposite effects. NFIB and CD44 were identified as novel targets of miR-302a. miR-302a inhibited the metastasis-promoting effect of NFIB that physiologically activates ITGA6 transcription. miR-302a restored CTX responsiveness by suppressing CD44-induced cancer stem cell-like properties and EGFR-mediated MAPK and AKT signaling. These results are consistent with clinical observations indicating that miR-302a expression is inversely correlated with the expression of its targets in CRC specimens. : Our findings show that miR-302a acts as a multifaceted regulator of CRC metastasis and CTX resistance by targeting NFIB and CD44, respectively. Our study implicates miR-302a as a candidate prognostic predictor and a therapeutic agent in CRC.
© The author(s).
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13 MeSH Terms
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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Monitoring Therapeutic Response and Resistance: Analysis of Circulating Tumor DNA in Patients With ALK+ Lung Cancer.
Horn L, Whisenant JG, Wakelee H, Reckamp KL, Qiao H, Leal TA, Du L, Hernandez J, Huang V, Blumenschein GR, Waqar SN, Patel SP, Nieva J, Oxnard GR, Sanborn RE, Shaffer T, Garg K, Holzhausen A, Harrow K, Liang C, Lim LP, Li M, Lovly CM
(2019) J Thorac Oncol 14: 1901-1911
MeSH Terms: Adult, Aged, Aged, 80 and over, Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung, Circulating Tumor DNA, Drug Resistance, Neoplasm, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Oncogene Proteins, Fusion, Piperazines, Prognosis, Protein Kinase Inhibitors, Pyridazines
Show Abstract · Added March 18, 2020
INTRODUCTION - Despite initial effectiveness of ALK receptor tyrosine kinase inhibitors (TKIs) in patients with ALK+ NSCLC, therapeutic resistance will ultimately develop. Serial tracking of genetic alterations detected in circulating tumor DNA (ctDNA) can be an informative strategy to identify response and resistance. This study evaluated the utility of analyzing ctDNA as a function of response to ensartinib, a potent second-generation ALK TKI.
METHODS - Pre-treatment plasma was collected from 76 patients with ALK+ NSCLC who were ALK TKI-naive or had received prior ALK TKI, and analyzed for specific genetic alterations. Longitudinal plasma samples were analyzed from a subset (n = 11) of patients. Analysis of pre-treatment tumor biopsy specimens from 22 patients was compared with plasma.
RESULTS - Disease-associated genetic alterations were detected in 74% (56 of 76) of patients, the most common being EML4-ALK. Concordance of ALK fusion between plasma and tissue was 91% (20 of 22 blood and tissue samples). Twenty-four ALK kinase domain mutations were detected in 15 patients, all had previously received an ALK TKI; G1269A was the most prevalent (4 of 24). Patients with a detectable EML4-ALK variant 1 (V1) fusion had improved response (9 of 17 patients; 53%) to ensartinib compared to patients with EML4-ALK V3 fusion (one of seven patients; 14%). Serial changes in ALK alterations were observed during therapy.
CONCLUSIONS - Clinical utility of ctDNA was shown, both at pre-treatment by identifying a potential subgroup of ALK+ NSCLC patients who may derive more benefit from ensartinib and longitudinally by tracking resistance. Prospective application of this technology may translate to improved outcomes for NSCLC patients treated with ALK TKIs.
Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.
Shi Y, Gao W, Lytle NK, Huang P, Yuan X, Dann AM, Ridinger-Saison M, DelGiorno KE, Antal CE, Liang G, Atkins AR, Erikson G, Sun H, Meisenhelder J, Terenziani E, Woo G, Fang L, Santisakultarm TP, Manor U, Xu R, Becerra CR, Borazanci E, Von Hoff DD, Grandgenett PM, Hollingsworth MA, Leblanc M, Umetsu SE, Collisson EA, Scadeng M, Lowy AM, Donahue TR, Reya T, Downes M, Evans RM, Wahl GM, Pawson T, Tian R, Hunter T
(2019) Nature 569: 131-135
MeSH Terms: Animals, Antibodies, Monoclonal, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Differentiation, Cell Line, Tumor, Disease Progression, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Female, Humans, Leukemia Inhibitory Factor, Male, Mass Spectrometry, Mice, Pancreatic Neoplasms, Paracrine Communication, Receptors, OSM-LIF, Tumor Microenvironment
Show Abstract · Added March 13, 2021
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance. Furthermore, PSC activation occurs very early during PDAC tumorigenesis, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.
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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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On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation.
Brown BP, Zhang YK, Westover D, Yan Y, Qiao H, Huang V, Du Z, Smith JA, Ross JS, Miller VA, Ali S, Bazhenova L, Schrock AB, Meiler J, Lovly CM
(2019) Clin Cancer Res 25: 3341-3351
MeSH Terms: Acrylamides, Alleles, Aniline Compounds, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, ErbB Receptors, Exons, Gene Expression Profiling, Humans, Lung Neoplasms, Models, Molecular, Mutation, Protein Binding, Protein Kinase Inhibitors, Structure-Activity Relationship
Show Abstract · Added March 21, 2020
PURPOSE - The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with -mutant lung cancer. Despite the development of highly selective third-generation inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in screens. Here, we investigate how G724S confers resistance to osimertinib. We combine structure-based predictive modeling of G724S in combination with the 2 most common EGFR-activating mutations, exon 19 deletion (Ex19Del) and L858R, with drug-response models and patient genomic profiling.
RESULTS - Our simulations suggest that the G724S mutation selectively reduces osimertinib-binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, whereas cells transduced with L858R/G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse.
CONCLUSIONS - Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the "drug-resistance mutation" pair to one focused on the "activating mutation-drug-resistance mutation" trio. This has broad implications across clinical oncology.
©2019 American Association for Cancer Research.
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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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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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Small Cell Lung Cancer Transformation as a Mechanism of Resistance to PD-1 Therapy in KRAS-Mutant Lung Adenocarcinoma: A Report of Two Cases.
Iams WT, Beckermann KE, Almodovar K, Hernandez J, Vnencak-Jones C, Lim LP, Raymond CK, Horn L, Lovly CM
(2019) J Thorac Oncol 14: e45-e48
MeSH Terms: Adenocarcinoma of Lung, Aged, Antineoplastic Agents, Immunological, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Female, Humans, Lung Neoplasms, Mutation, Prognosis, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins p21(ras), Small Cell Lung Carcinoma
Added September 10, 2020
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