Molecular pathway activation – New type of biomarkers for tumor morphology and personalized selection of target drugs

Buzdin, Anton; Sorokin, Maxim; Garazha, Andrew; Sekacheva, Marina; Kim, Ella; Жуков, Н. В.; Wang, Ye; Li, Xinmin; Kar, Souvik; Hartmann, Christian; Samii, Amir; Giese, Alf; Borisov, Nicolas

doi:10.1016/j.semcancer.2018.06.003

Cited by 89 publications

(85 citation statements)

References 139 publications

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“…Molecular classification of tumors is a promising field in cancer research that can bring new diagnostic, prognostic and therapeutic options along with improved treatment outcomes [60]. High throughput sequencing provides an instrument for modern classification of tumors based on whole exome mutation profiles and/or gene expression data.…”

Section: Discussionmentioning

confidence: 99%

Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology

Zolotovskaia

Sorokin

Petrov³

et al. 2020

IJMS

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Inter-patient molecular heterogeneity is the major declared driver of an expanding variety of anticancer drugs and personalizing their prescriptions. Here, we compared interpatient molecular heterogeneities of tumors and repertoires of drugs or their molecular targets currently in use in clinical oncology. We estimated molecular heterogeneity using genomic (whole exome sequencing) and transcriptomic (RNA sequencing) data for 4890 tumors taken from The Cancer Genome Atlas database. For thirteen major cancer types, we compared heterogeneities at the levels of mutations and gene expression with the repertoires of targeted therapeutics and their molecular targets accepted by the current guidelines in oncology. Totally, 85 drugs were investigated, collectively covering 82 individual molecular targets. For the first time, we showed that the repertoires of molecular targets of accepted drugs did not correlate with molecular heterogeneities of different cancer types. On the other hand, we found that the clinical recommendations for the available cancer drugs were strongly congruent with the gene expression but not gene mutation patterns. We detected the best match among the drugs usage recommendations and molecular patterns for the kidney, stomach, bladder, ovarian and endometrial cancers. In contrast, brain tumors, prostate and colorectal cancers showed the lowest match. These findings provide a theoretical basis for reconsidering usage of targeted therapeutics and intensifying drug repurposing efforts.

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Section: Discussionmentioning

confidence: 99%

Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology

Zolotovskaia

Sorokin

Petrov³

et al. 2020

IJMS

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“…Breast cancer had serious adverse effects on the prognosis of patients (Dai et al, 2017). In recent years, proposal of molecular biomarkers had provided important clues for targeted therapy of breast cancer as well as other malignant tumors (Buzdin et al, 2018;Kutomi et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

LINC01857 as an oncogene regulates CREB1 activation by interacting with CREBBP in breast cancer

Xiong

Wang

et al. 2019

Journal Cellular Physiology

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Breast cancer is a one of the most malignant threats among women worldwide. However, the mechanism underlying breast cancer development remains unclear. Long noncoding RNAs (lncRNAs) have been reported to participate in breast cancer. Whether lncRNA LINC01857 is involved in breast cancer requires investigation. In this study, we found that LINC01857 was highly expressed in breast cancer tissues and cells (p < 0.05). High LINC01857 expression predicted poor prognosis in breast cancer patients. Functionally, LINC01857 silencing impaired proliferation and enhanced apoptosis of breast cancer cells ( p < 0.05). Decreased LINC01857 inhibited breast cancer cells migration and invasion ability ( p < 0.05). In terms of mechanism, LINC01857 promoted H3K27Ac deposition on CREB1 promoter and initiated its transcription by recruiting CREBBP. Overexpression of CREB1 reversed the biological behavior of breast cancer cells induced by LINC01857 silencing ( p < 0.05). Taken together, our findings demonstrated that LINC01857 promoted breast cancer development by promoting H3K27Ac and CREB1 transcription via enhancing CREBBP enrichment in the CREB1 promoter region.

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“…Alterations in activation of intracellular molecular pathways relatively to normal samples were quantitatively assessed using the bioinformatical platform Oncobox. 10 The structures of 3121 molecular pathways were extracted from the following public databases: Reactome, 11 NCI Pathway Interaction Database, 12 Kyoto Encyclopedia of Genes and Genomes, 13 HumanCyc, 14 Biocarta [www.biocarta. com] and Qiagen (www.qiagen.com/ us/shop/ genes-and-pathways/pathway-central/).…”

Section: Bioinformatic Analysis Of Proteomic Datamentioning

confidence: 99%

“…Similarly, we calculated activation levels of 3118 molecular pathways using Oncobox algorithm that quantitatively estimates activation of molecular pathways. 10,20 Pathway activation level (PAL) values were calculated for three cell lines tested in comparison with the control samples using quantitative proteomics expression data (supplementary Table 1). Positive values of PAL score indicate down-regulation of a pathway, and vice versa, negative values mean downregulation of a pathway.…”

Section: Protein Expression Analysis and Molecular Pathway Activationmentioning

confidence: 99%

Molecular heterogeneity in breast carcinoma cells with increased invasive capacities

Negro

Aschenbrenner

Kranjc

et al. 2020

Radiology and Oncology

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BackgroundMetastatic progression of breast cancer is still a challenge in clinical oncology. Therefore, an elucidation how carcinoma cells belonging to different breast cancer subtypes realize their metastatic capacities is needed. The aim of this study was to elucidate a similarity of activated molecular pathways underlying an enhancement of invasiveness of carcinoma cells belonging to different breast carcinoma subtypes.Materials and methodsIn order to reach this aim, parental and invasive (INV) MDA-MB-231 (triple-negative), T47D (hormone receptor-positive), and Au565 (Her2-positive) breast carcinoma cells were used and their molecular phenotypes were compared using a proteomic approach.ResultsIndependently from breast cancer subtypes, INV cells have demonstrated fibroblast-like morphology accompanied by enhancement of invasive and migratory capacities, increased expression of cancer stem cell markers, and delayed tumor growth in in vivo animal models. However, the global proteomic analysis has highlighted that INV cells were different in protein expressions from the parental cells, and Her2-positive Au565-INV cells showed the most pronounced molecular differences compared to the triple-negative MDA-MB-231-INV and hormone receptor-positive T47D-INV cells. Although Au565-INV breast carcinoma cells possessed the highest number of deregulated proteins, they had the lowest overlapping in proteins commonly expressed in MDA-MB-231-INV and T47D-INV cells.ConclusionsWe can conclude that hormone receptor-positive cells with increased invasiveness acquire the molecular characteristics of triple-negative breast cancer cells, whereas Her2-positive INV cells specifically changed their own molecular phenotype with very limited partaking in the involved pathways found in the MDA-MB-231-INV and T47D-INV cells. Since hormone receptor-positive invasive cells share their molecular properties with triple-negative breast cancer cells, we assume that these types of metastatic disease can be treated rather equally with an option to add anti-hormonal agents. In contrast, Her2-positive metastasis should be carefully evaluated for more effective therapeutic approaches which are distinct from the triple-negative and hormone-positive metastatic breast cancers.

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Molecular pathway activation – New type of biomarkers for tumor morphology and personalized selection of target drugs

Cited by 89 publications

References 139 publications

Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology

Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology

LINC01857 as an oncogene regulates CREB1 activation by interacting with CREBBP in breast cancer

Molecular heterogeneity in breast carcinoma cells with increased invasive capacities

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