AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy

Bertrán-Alamillo, Jordi; Cattan, Valérie; Schoumacher, Marie; Codony-Servat, Jordi; Giménez‐Capitán, Ana; Cantero, Frédérique; Burbridge, Mike F.; Rodríguez, Sónia; Teixidó, Cristina; Román, Ruth; Castellví, Josep; García-Román, Silvia; Codony-Servat, Carles; Viteri, Santiago; Cardona, Andrés-Felipe; Karachaliou, Niki; Rosell, Rafael; Molina-Vila, M.A.

doi:10.1038/s41467-019-09734-5

Cited by 104 publications

(82 citation statements)

References 50 publications

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“…Here, all of the mutual interactors of Survivin exhibited significant regulation, which led to a reduced expression of these molecules in Pirfenidone treated A549 cells ( Figure 4B). Furthermore, Survivin/BIRC5 interacted closely with molecules ( Figure 4C) which were shown to regulate stem cell properties in lung adenocarcinomas (SPC25) (28), influence radiosensitivity in lung cancer (AURKA) (29), or mediate anti-EGFR therapy in NSCLC (AURKB) (30). Interestingly, a majority of Survivin interacting molecules that were found to be significantly regulated by Pirfenidone are also associated with the mitotic spindle (MAD2L1, BUB1, BUB1B, BUB3, CDC20) and were shown to be increased in human breast cancer (31).…”

Section: Pirfenidone Down-regulated Survivin Affected Apoptotic Signmentioning

confidence: 99%

The Multi-Modal Effect of the Anti-fibrotic Drug Pirfenidone on NSCLC

et al. 2020

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Although immune checkpoint and targeted therapies offer remarkable benefits for lung cancer treatment, some patients do not qualify for these regimens or do not exhibit consistent benefit. Provided that lung cancer appears to be driven by transforming growth factor beta signaling, we investigated the single drug potency of Pirfenidone, an approved drug for the treatment of lung fibrosis. Five human lung cancer cell lines and one murine line were investigated for transforming growth factor beta inhibition via Pirfenidone by using flow cytometry, In-Cell western analysis, proliferation assays as well as comprehensive analyses of the transcriptome with subsequent bioinformatics analysis. Overall, Pirfenidone induced cell cycle arrest, down-regulated SMAD expression and reduced proliferation in lung cancer. Furthermore, cell stress pathways and pro-apoptotic signaling may be mediated by reduced expression of Survivin. A murine subcutaneous model was used to assess the in vivo drug efficacy of Pirfenidone and showed reduced tumor growth and increased infiltration of T cells and NK cells. This data warrant further clinical evaluation of Pirfenidone with advanced non-small cell lung cancer. The observed in vitro and in vivo effects point to a substantial benefit for using Pirfenidone to reactivate the local immune response and possible application in conjunction with current immunotherapies.

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Section: Pirfenidone Down-regulated Survivin Affected Apoptotic Signmentioning

confidence: 99%

The Multi-Modal Effect of the Anti-fibrotic Drug Pirfenidone on NSCLC

et al. 2020

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“…Finally we could show the importance of CDK2 as a master regulator of many kinases and transcription factors such as MYC, AURKB, E2F4 and consequently TP53 and ATM activities ( Figure 4 D ). In particular, AURKB, which directly controls TP53 and ATM activities, appears to be a promising marker of kidney cancer [46][47][48] .…”

Section: Discussionmentioning

confidence: 99%

Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses

Dugourd

Kuppe

Sciacovelli

et al. 2020

Preprint

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Multi-omics datasets can provide molecular insights beyond the sum of individual omics.Diverse tools have been recently developed to integrate such datasets, but there are limited strategies to systematically extract mechanistic hypotheses from them. Here, we present COSMOS (Causal Oriented Search of Multi-Omics Space), a method that integrates phosphoproteomics, transcriptomics, and metabolics datasets. COSMOS combines extensive prior knowledge of signaling, metabolic, and gene regulatory networks with computational methods to estimate activities of transcription factors and kinases as well as network-level causal reasoning. COSMOS provides mechanistic hypotheses for experimental observations across multi-omics datasets. We applied COSMOS to a dataset comprising transcriptomics, phosphoproteomics, and metabolomics data from healthy and cancerous tissue from nine renal cell carcinoma patients. We used COSMOS to generate novel hypotheses such as the impact of Androgen Receptor on nucleoside metabolism and the influence of the JAK-STAT pathway on propionyl coenzyme A production. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi-omics studies.

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“…AURKB is also involved in resistance to specific anti-tumor agents, such as paclitaxel in NSCLC 45 . Bertran-Alamillo et al revealed that AURKB is related to acquired resistance to EGFR TKIs, and AURKB can become a potential biological target for anti- EGFR therapy of NSCLC without carrying resistance mutations 46 .…”

Section: Discussionmentioning

confidence: 99%

Independent prognostic implications of RRM2 in lung adenocarcinoma

Luo

Cao

et al. 2020

J. Cancer

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Background: Ribonucleoside-diphosphate reductase subunit M2 ( RRM2 ) is the catalytic subunit of ribonucleotide reductase and modulates the enzymatic activity, which is essential for DNA replication and repair. However, the role of RRM2 in lung adenocarcinoma (LUAD) remains unclear. Methods: In this study, we explored the expression pattern and prognostic value of RRM2 in LUAD across TCGA, GEO, Oncomine, UALCAN, PrognoScan, and Kaplan-Meier Plotter, and confirmed its independent prognostic value via Cox analyses. LinkedOmics and GEPIA2 were applied to investigate co-expression and functional networks associated with RRM2 . Besides, we used TIMER to assess the correlation between RRM2 and the main six types of tumor-infiltrating immune cells. Lastly, the correlations between immune signatures of immunomodulators, chemokines, and 28 tumor-infiltrating lymphocytes (TILs) and RRM2 were examined by tumor purity-corrected partial Spearman's rank correlation coefficient through TIMER portal. Results: RRM2 was found upregulated in tumor tissues in TCGA-LUAD, and validated in multiple independent cohorts. Moreover, whether in TCGA or other cohorts, high RRM2 expression was found to be associated with poor survival. Cox analyses showed that high RRM2 expression was an independent risk factor for overall survival, disease-specific survival, and progression-free survival of LUAD. Functional network analysis suggested that RRM2 regulates RNA transport, oocyte meiosis, spliceosome, ribosome biogenesis in eukaryotes, and cellular senescence signaling through pathways involving multiple cancer-related kinases and E2F family. Also, RRM2 expression correlated with infiltrating levels of B cells, CD4+ T cells, and neutrophils. Subsequent analysis found that B cells and dendritic cells could predict the outcome of LUAD. B cells were identified as an independent risk factor among six types of immune cells through Cox analyses. At last, the correlation analysis showed RRM2 correlated with 67.68% (624/922) of the immune signatures we performed. Conclusion: Our research showed that RRM2 could independently predict the prognosis of LUAD and was associated with immune infiltration. In particular, the tight relationship between RRM2 and B cell marker genes are the potential epicenter of the immune response and one of the critical factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of RRM2 in LUAD.

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AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy

Cited by 104 publications

References 50 publications

The Multi-Modal Effect of the Anti-fibrotic Drug Pirfenidone on NSCLC

The Multi-Modal Effect of the Anti-fibrotic Drug Pirfenidone on NSCLC

Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses

Independent prognostic implications of RRM2 in lung adenocarcinoma

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