Abstract 2226: Prioritizing tumor types for clinical study of novel Sec61 inhibitors by searching for expression profiles of sensitive cell lines in tumor sample databases

3011 Background: Ixabepilone is a microtubule stabilizing agent with significant therapeutic value in breast cancer (BC) patients. To identify predictive biomarkers capable of identifying patients likely to receive optimal benefit from ixabepilone treatment, preclinical and clinical studies were carried out. Several biomarkers discovered using preclinical models were validated in a neoadjuvant BC clinical study ( CA163080 ) and one, estrogen receptor 1 (ER), was shown to double the pathological complete response (pCR) rate in patients treated with ixabepilone. To identify candidate sets of biomarkers that could further increase the pCR rate we have performed post-hoc analyses of the preclinical and clinical data. Methods: Eighteen BC cell lines were classified as sensitive or resistant (S/R) based on the IC50 values for ixabepilone treatment. Gene expression profiling of the BC cell lines was conducted and genes correlated with the S/R classification were identified using a k-Nearest Neighbors algorithm. Patients in clinical study CA163080 underwent a pretreatment core needle biopsy from which RNA was isolated and gene expression profiles generated (data available on 134 patients). Analyses using the preclinical and clinical markers were conducted using various statistical tools. Results: Several markers used in combination with ER were found to be capable of tripling the pCR to ixabepilone in CA163080. In addition to ER other predictive markers were identified that were as predictive as ER, including several genes whose expression is anti-correlated with ER and are part of the ER pathway. Finally, various sub-group analyses were performed and manifested the importance of clinical sample variation that needs to be considered for the analysis. Conclusions: Several single biomarkers identified from preclinical studies were validated in the clinical study CA163080 , demonstrating the utility of this approach. Such markers can be used in combination to better identify patients likely to respond to ixabepilone in future clinical trials. Furthermore, molecular response markers that can be tied to the mechanism of drug resistance can be used for further developing chemotherapy in drug development. [Table: see text]

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Expression Atlas of FGF and FGFR Genes in Pancancer Uncovered Predictive Biomarkers for Clinical Trials of Selective FGFR Inhibitors

BioMed Research International ◽

10.1155/2020/5658904 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yuan Li ◽

Long Wu ◽

Weiping Tao ◽

Dawei Wu ◽

Fei Ma ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Trials ◽

Tumor Cell ◽

Cell Lines ◽

Expression Profiles ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Tumor Cell Lines ◽

Expression Atlas ◽

Tumor Types

Background. Clinical trials based on FGFR mutation or amplification as a druggable target of FGFR inhibitors have produced disappointing clinical outcomes. Therefore, the identification of predictive biomarkers for FGFR-targeted agents has remained a crucial issue. Methods. Expression profiles of FGFs and FGFRs in 8,111 patients with 24 types of solid tumors and 879 tumor cell lines along with drug sensitivity data were obtained and followed by integrative bioinformatics analysis. Results. FGFs and FGFRs were frequently dysregulated in pancancer. Most of the expression of FGFs and FGFRs were significantly associated with overall survival in at least two cancer types. Moreover, tumor cell lines with high FGFR1/3 expression were more sensitive to FGFR inhibitor PD173074, especially in breast, liver, lung and ovarian cancer. The predicted positive ratios of FGFR1-4 were generally over 10% in most tumor types, especially in squamous cell carcinoma. High positive FGFR1 or 3 expression ratios were predicted in cholangiocarcinoma (58%), followed by bladder cancer (42%), endometrial carcinoma (35%), and ovarian cancer (34%). Conclusions. FGFR expression was a promising predictive biomarker for FGFR inhibition response in clinical trials, and different combinations of FGFR genes should be used in screening for patients in certain tumor types.

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Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer

Genes ◽

10.3390/genes12050615 ◽

2021 ◽

Vol 12 (5) ◽

pp. 615

Author(s):

Achala Fernando ◽

Chamikara Liyanage ◽

Afshin Moradi ◽

Panchadsaram Janaththani ◽

Jyotsna Batra

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Expression Profiles ◽

Association Studies ◽

Protein Isoforms ◽

The Cancer Genome Atlas ◽

Mass Spectrometry Analysis ◽

Functional Domains ◽

Homeodomain Protein ◽

Genome Wide Association Studies

Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans. However, tumor growth, metastasis and therapy resistance benefit from aberrant RNA splicing. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies. In the current study, we characterized 12 IRX4 transcripts in PCa cell lines, including seven novel transcripts by RT-PCR and sequencing. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. These transcripts were significantly overexpressed in PCa cell lines and the cancer genome atlas program (TCGA) PCa clinical specimens, suggesting their probable involvement in PCa progression. Moreover, a PCa risk-associated SNP rs12653946 genotype GG was corelated with lower IRX4 transcript levels. Using mass spectrometry analysis, we identified two IRX4 protein isoforms (54.4 kDa, 57 kDa) comprising all the functional domains and two novel isoforms (40 kDa, 8.7 kDa) lacking functional domains. These IRX4 isoforms might induce distinct functional programming that could contribute to PCa hallmarks, thus providing novel insights into diagnostic, prognostic and therapeutic significance in PCa management.

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Genome-Wide Role of HSF1 in Transcriptional Regulation of Desiccation Tolerance in the Anhydrobiotic Cell Line, Pv11

International Journal of Molecular Sciences ◽

10.3390/ijms22115798 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5798

Author(s):

Shoko Tokumoto ◽

Yugo Miyata ◽

Ruslan Deviatiiarov ◽

Takahiro G. Yamada ◽

Yusuke Hiki ◽

...

Keyword(s):

Cell Line ◽

Cell Lines ◽

Desiccation Tolerance ◽

Expression Profiles ◽

Insect Cell Line ◽

Gene Expression Profiles ◽

Late Embryogenesis Abundant ◽

Heat Shock Factor 1 ◽

Genome Wide ◽

A Genome

The Pv11, an insect cell line established from the midge Polypedilum vanderplanki, is capable of extreme hypometabolic desiccation tolerance, so-called anhydrobiosis. We previously discovered that heat shock factor 1 (HSF1) contributes to the acquisition of desiccation tolerance by Pv11 cells, but the mechanistic details have yet to be elucidated. Here, by analyzing the gene expression profiles of newly established HSF1-knockout and -rescue cell lines, we show that HSF1 has a genome-wide effect on gene regulation in Pv11. The HSF1-knockout cells exhibit a reduced desiccation survival rate, but this is completely restored in HSF1-rescue cells. By comparing mRNA profiles of the two cell lines, we reveal that HSF1 induces anhydrobiosis-related genes, especially genes encoding late embryogenesis abundant proteins and thioredoxins, but represses a group of genes involved in basal cellular processes, thus promoting an extreme hypometabolism state in the cell. In addition, HSF1 binding motifs are enriched in the promoters of anhydrobiosis-related genes and we demonstrate binding of HSF1 to these promoters by ChIP-qPCR. Thus, HSF1 directly regulates the transcription of anhydrobiosis-related genes and consequently plays a pivotal role in the induction of anhydrobiotic ability in Pv11 cells.

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Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines

Oncogene ◽

10.1038/sj.onc.1205829 ◽

2002 ◽

Vol 21 (42) ◽

pp. 6549-6556 ◽

Cited By ~ 39

Author(s):

Jiafu Ji ◽

Xin Chen ◽

Suet Yi Leung ◽

Jen-Tsan A Chi ◽

Kent Man Chu ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Gastric Cancer Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Comprehensive Analysis ◽

Human Gastric Cancer ◽

Gastric Cancer Cell Lines

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Robust Metabolic Transcriptional Components in 34,494 Patient-Derived Samples and Cell Lines

10.21203/rs.3.rs-659596/v1 ◽

2021 ◽

Author(s):

Vincent Christiaan Leeuwenburgh ◽

Carlos G. Urzúa-Traslaviña ◽

Arkajyoti Bhattacharya ◽

Marthe T.C. Walvoort ◽

Mathilde Jalving ◽

...

Keyword(s):

Cell Lines ◽

Expression Profiles ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Metabolic Processes ◽

Gene Sets ◽

Transcriptional Changes ◽

Cancer Tissues ◽

Tumor Biopsies ◽

Transcriptional Landscape

Abstract Background: Patient-derived bulk expression profiles of cancers can provide insight into transcriptional changes that underlie reprogrammed metabolism in cancer. These profiles represent the average expression pattern of all heterogeneous tumor and non-tumor cells present in biopsies of tumor lesions. Hence, subtle transcriptional footprints of metabolic processes can be concealed by other biological processes and experimental artifacts. However, consensus Independent Component Analyses (c-ICA) can capture statistically independent transcriptional footprints, of both subtle and more pronounced metabolic processes. Methods: We performed c-ICA with 34,494 bulk expression profiles of patient-derived tumor biopsies, non-cancer tissues, and cell lines. Gene set enrichment analysis with 608 gene sets that describe metabolic processes was performed to identify transcriptional components enriched for metabolic processes (mTCs). The activity of these mTCs were determined in all samples to create a metabolic transcriptional landscape. Results: A set of 555 mTCs were identified of which many were robust across different datasets, platforms, and patient-derived tissues and cell lines. We demonstrate how the metabolic transcriptional landscape defined by the activity of these mTCs in samples can be used to explore associations between the metabolic transcriptome and drug sensitivities, patient outcomes, and the composition of the immune tumor microenvironment. Conclusions: To facilitate the use of our transcriptional metabolic landscape, we have provided access to all data via a web portal ( www.themetaboliclandscapeofcancer.com ). We believe this resource will contribute to the formulation of new hypotheses on how to metabolically engage the tumor or its (immune) microenvironment.

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Expression Profiles of microRNAs in Drug-Resistant Non-Small Cell Lung Cancer Cell Lines Using microRNA Sequencing

Cellular Physiology and Biochemistry ◽

10.1159/000495921 ◽

2018 ◽

Vol 51 (6) ◽

pp. 2509-2522 ◽

Cited By ~ 9

Author(s):

Shousen Hu ◽

Yongliang Yuan ◽

Zhizhen Song ◽

Dan Yan ◽

Xiangzhen Kong

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Expression Profiles ◽

Small Cell ◽

Nsclc Cell ◽

Drug Resistant ◽

Small Cell Lung

Background/Aims: Drug resistance remains a main obstacle to the treatment of non- small cell lung cancer (NSCLC). The aim of this study was to identify the expression profiles of microRNAs (miRNAs) in drug-resistant NSCLC cell lines. Methods: The expression profiles of miRNAs in drug-resistant NSCLC cell lines were examined using miRNA sequencing, and the common dysregulated miRNAs in these cell lines were identified and analyzed by bioinformatics methods. Results: A total of 29 upregulated miRNAs and 36 downregulated miRNAs were found in the drug-resistant NSCLC cell lines, of which 26 upregulated and 36 downregulated miRNAs were found to be involved in the Ras signaling pathway. The expression levels, survival analysis, and receiver operating characteristic curve of the dysregulated miRNAs based on The Cancer Genome Atlas database for lung adenocarcinoma showed that hsa-mir-192, hsa-mir-1293, hsa-mir-194, hsa-mir-561, hsa-mir-205, hsa-mir-30a, and hsa-mir-30c were related to lung cancer, whereas only hsa-mir-1293 and hsa-mir-561 were not involved in drug resistance. Conclusion: The results of this study may provide novel biomarkers for drug resistance in NSCLC and potential therapies for overcoming drug resistance, and may also reveal the potential mechanisms underlying drug resistance in this disease.

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Proton-irradiated breast cells: molecular points of view

Journal of Radiation Research ◽

10.1093/jrr/rrz032 ◽

2019 ◽

Vol 60 (4) ◽

pp. 451-465 ◽

Cited By ~ 3

Author(s):

Valentina Bravatà ◽

Francesco P Cammarata ◽

Luigi Minafra ◽

Pietro Pisciotta ◽

Concetta Scazzone ◽

...

Keyword(s):

Cell Line ◽

Cell Fate ◽

Cell Lines ◽

Molecular Mechanisms ◽

Proton Irradiation ◽

Expression Profiles ◽

Treatment Plan ◽

Mcf10a Cell ◽

Specific Cell ◽

Dose Dependent

Abstract Breast cancer (BC) is the most common cancer in women, highly heterogeneous at both the clinical and molecular level. Radiation therapy (RT) represents an efficient modality to treat localized tumor in BC care, although the choice of a unique treatment plan for all BC patients, including RT, may not be the best option. Technological advances in RT are evolving with the use of charged particle beams (i.e. protons) which, due to a more localized delivery of the radiation dose, reduce the dose administered to the heart compared with conventional RT. However, few data regarding proton-induced molecular changes are currently available. The aim of this study was to investigate and describe the production of immunological molecules and gene expression profiles induced by proton irradiation. We performed Luminex assay and cDNA microarray analyses to study the biological processes activated following irradiation with proton beams, both in the non-tumorigenic MCF10A cell line and in two tumorigenic BC cell lines, MCF7 and MDA-MB-231. The immunological signatures were dose dependent in MCF10A and MCF7 cell lines, whereas MDA-MB-231 cells show a strong pro-inflammatory profile regardless of the dose delivered. Clonogenic assay revealed different surviving fractions according to the breast cell lines analyzed. We found the involvement of genes related to cell response to proton irradiation and reported specific cell line- and dose-dependent gene signatures, able to drive cell fate after radiation exposure. Our data could represent a useful tool to better understand the molecular mechanisms elicited by proton irradiation and to predict treatment outcome

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Aberrant Long Noncoding RNAs Expression Profiles Affect Cisplatin Resistance in Lung Adenocarcinoma

BioMed Research International ◽

10.1155/2017/7498151 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Lijuan Hu ◽

Jian Chen ◽

Fan Zhang ◽

Junjun Wang ◽

Jingye Pan ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

A549 Cell ◽

Cisplatin Resistance ◽

Expression Profiles ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Pcr Analysis ◽

Sensitive Cell ◽

Chain Reaction ◽

Polymerase Chain

Background. Long noncoding RNAs (lncRNAs) have been shown to be involved in the mechanism of cisplatin resistance in lung adenocarcinoma (LAD). However, the roles of lncRNAs in cisplatin resistance in LAD are not well understood. Methods. We used a high-throughput microarray to compare the lncRNA and mRNA expression profiles in cisplatin resistance cell A549/DDP and cisplatin sensitive cell A549. Several candidate cisplatin resistance-associated lncRNAs were verified by real-time quantitative reverse transcription polymerase chain reaction (PCR) analysis. Results. We found that 1,543 lncRNAs and 1,713 mRNAs were differentially expressed in A549/DDP cell and A549 cell, hinting that many lncRNAs were irregular from cisplatin resistance in LAD. We also obtain the fact that 12 lncRNAs were aberrantly expressed in A549/DDP cell compared with A549 cell by quantitative PCR. Among these, UCA1 was the aberrantly expressed lncRNA and can significantly reduce the IC50 of cisplatin in A549/DDP cell after knockdown, while it can increase the IC50 of cisplatin after UCA1 was overexpressed in NCI-H1299. Conclusions. We obtained patterns of irregular lncRNAs and they may play a key role in cisplatin resistance of LAD.

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Expression Profiling of Nuclear Receptors in the NCI60 Cancer Cell Panel Reveals Receptor-Drug and Receptor-Gene Interactions

Molecular Endocrinology ◽

10.1210/me.2010-0040 ◽

2010 ◽

Vol 24 (6) ◽

pp. 1287-1296 ◽

Cited By ~ 49

Author(s):

Susan Holbeck ◽

Jianjun Chang ◽

Anne M. Best ◽

Angie L. Bookout ◽

David J. Mangelsdorf ◽

...

Keyword(s):

Drug Interactions ◽

Cell Lines ◽

Nuclear Receptors ◽

Cancer Cell ◽

Expression Profiling ◽

Expression Profiles ◽

Receptor Gene ◽

Receptor Expression ◽

Cancer Drug ◽

Mrna Levels

Abstract We profiled the expression of the 48 human nuclear receptors (NRs) by quantitative RT-PCR in 51 human cancer cell lines of the NCI60 collection derived from nine different tissues. NR mRNA expression accurately classified melanoma, colon, and renal cancers, whereas lung, breast, prostate, central nervous system, and leukemia cell lines exhibited heterogeneous receptor expression. Importantly, receptor mRNA levels faithfully predicted the growth-inhibitory qualities of receptor ligands in nonendocrine tumors. Correlation analysis using NR expression profiles and drug response information across the cell line panel uncovered a number of new potential receptor-drug interactions, suggesting that in these cases, individual receptor levels may predict response to chemotherapeutic interventions. Similarly, by cross-comparing receptor levels within our expression dataset and relating these profiles to existing microarray gene expression data, we defined interactions among receptors and between receptors and other genes that can now be mechanistically queried. This work supports the strategy of using NR expression profiling to classify various types of cancer, define NR-drug interactions and receptor-gene networks, predict cancer-drug sensitivity, and identify druggable targets that may be pharmacologically manipulated for potential therapeutic intervention.

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