Decreased levels of baseline and drug-induced tubulin polymerisation are hallmarks of resistance to taxanes in ovarian cancer cells and are associated with epithelial-to-mesenchymal transition

Durán, George E.; Wang, Yan C.; Moisan, François; Francisco, E. Brian; Šikić, Branimir I.

doi:10.1038/bjc.2017.102

Cited by 38 publications

(37 citation statements)

References 42 publications

(65 reference statements)

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“…The BCL2 and BCL2L1 (BCL‐xL) genes reached high significance in both Basal and Luminal A samples. Overexpression of BCL2 was recently linked to paclitaxel resistance in cell lines . Tumors with higher BCL2L1 expression had shorter RFS times .…”

Section: Discussionmentioning

confidence: 99%

ROCplot.org: Validating predictive biomarkers of chemotherapy/hormonal therapy/anti‐HER2 therapy using transcriptomic data of 3,104 breast cancer patients

Fekete

Győrffy

2019

Intl Journal of Cancer

221

210

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Systemic therapy of breast cancer can include chemotherapy, hormonal therapy and targeted therapy. Prognostic biomarkers are able to predict survival and predictive biomarkers are able to predict therapy response. In this report, we describe the initial release of the first available online tool able to identify gene expression-based predictive biomarkers using transcriptomic data of a large set of breast cancer patients. Published gene expression data of 36 publicly available datasets were integrated with treatment data into a unified database. Response to therapy was determined using either author-reported pathological complete response data (n = 1,775) or relapse-free survival status at 5 years (n = 1,329). Treatment data includes chemotherapy (n = 2,108), endocrine therapy (n = 971) and anti-human epidermal growth factor receptor 2 (HER2) therapy (n = 267). The transcriptomic database includes 20,089 unique genes and 54,675 probe sets. Gene expression and therapy response are compared using receiver operating characteristics and Mann-Whitney tests. We demonstrate the utility of the pipeline by cross-validating 23 paclitaxel resistance-associated genes in different molecular subtypes of breast cancer. An additional set of established biomarkers including TP53 for chemotherapy in Luminal breast cancer (p = 1.01E-19, AUC = 0.769), HER2 for trastuzumab therapy (p = 8.4E-04, AUC = 0.629) and PGR for hormonal therapy (p = 8.6E-05, AUC = 0.7), are also endorsed. The tool is designed to validate and rank new predictive biomarker candidates in real time. By analyzing the selected genes in a large set of independent patients, one can select the most robust candidates and quickly eliminate those that are most likely to fail in a clinical setting. The analysis tool is accessible at www.rocplot.org.

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Section: Discussionmentioning

confidence: 99%

ROCplot.org: Validating predictive biomarkers of chemotherapy/hormonal therapy/anti‐HER2 therapy using transcriptomic data of 3,104 breast cancer patients

Fekete

Győrffy

2019

Intl Journal of Cancer

221

210

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ The combined regimen represents a promising option to increase the efficacy of PTX and to prevent its resistance also in patients receiving taxane-based first-line palliative chemotherapy 14 . Although PTX is widely used as a first-line agent in chemotherapies, several studies indicate factors such as microtubule organization, EMT phenotype and apoptotic resistance as the main causes of resistance to treatment with this drug [15][16][17][18][26][27][28][29][30] . In epithelial tumor cells, the binding of VEGFA to VEGFR2 sustains autocrine loop affecting cell growth and migration.…”

Section: Discussionmentioning

confidence: 99%

“…The synergistic effects were evidenced also by the analysis of β-tubulin III protein whose expression was significantly inhibited upon dual drug treatment. EMT protein expression analysis revealed that while epithelial marker E-Cadherin was overexpressed, the mesenchymal marker N-Cadherin was down regulated after combined drug treatment 18,26 . The VEGFA expression levels were unchanged in AGS and KATO III cells while an increase was observed in HGC-27 and N87 after single or dual drug treatments.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of synergistic action of Ramucirumab and Paclitaxel in Gastric Cancers cell lines

Refolo

Lotesoriere

Lolli

et al. 2020

Sci Rep

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Ramucirumab is approved both as monotherapy and in combination with paclitaxel for advanced gastric cancer in patients with disease progression after chemotherapy. in tumor cells, the VeGfA-VEGFR2 binding activates autocrine survival and migration signaling in angiogenesis independent manner. the present in vitro study investigated the effects of single and combined treatments with Ramucirumab and paclitaxel on cell growth and migration highlighting the mechanisms underlying the interaction between the two drugs in gastric cancer cells. cell growth and motility were investigated in human gastric cancer cell lines characterized by different tumorigenicity. The inhibitory effect on cell growth exerted by both drugs was potentiated by their combination and was synergistic. Ramucirumab was able to enhance the inhibitory effect exerted by Paclitaxel on cell cycle progression. A synergistic action was also observed in the expression of proteins crucial for cell motility, microtubule organization and epithelial-mesenchymal transition. Furthermore, synergistic inhibition of VEGFR2 expression was obtained by the drug combination. These findings highlighted the importance of the combined treatment to strongly inhibit all the main molecules of both PI3K/Akt/mTOR and MAPK pathways thus preventing possible reactivations due to cross-talk phenomena. The combined treatment with Ramucirumab seems to be a promising option to overcome the paclitaxel resistance.VEGFR2 plays a crucial role in gastric cancer pathogenesis and progression and Ramucirumab (Ram), a monoclonal antibody against VEGFR2, is the first antiangiogenic agent with demonstrated activity against advanced gastric cancer. Based on the results obtained by two different phase III studies, Ram is approved both as monotherapy and in combination with Paclitaxel (PTX) for this malignancy in patients with disease in progression after a preceding therapy based on platinum and fluoropyrimidin 1-5 .The proangiogenic actions of VEGFs in endothelial cells are mediated primarily through the binding and activation of VEGFR2 6 and retrospective studies considered VEGF and its receptors as possible biomarkers in gastric carcinoma 7-9 . Moreover, the recent discovery of the production of different VEGF ligands and of the expression of VEGFR1, VEGFR2 and VEGFR3 in epithelial cancer cells, suggests a direct role for these ligands and their receptors in the autocrine control of some biological processes. In epithelial tumor cells, the binding of VEGFA, the main ligand of VEGFR2, activates downstream survival and migration signaling pathways represented by PI3K/ Akt/mTOR and MAPK cascades in a cell autonomous and angiogenesis independent manner 10-13 .The combined treatment with Ram seems to be a promising option to prevent the resistance to PTX also in recurrent and metastatic gastric cancer patients receiving taxane-based first-line palliative chemotherapy 14 . PTX is known to interfere with microtubule architecture by binding to β-tubulin, thereby blocking cell cycle progression at th...

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“…Overexpressed β-tubulin III has been reported in numerous types of acquired PTX-resistant cancers 9 – 12 , but whether it is an unfavorable factor in GC is uncertain. According to published reports, acquired resistance to 1PTX in cancers involves other mechanisms, including altered drug efflux, epithelial–mesenchymal transition (EMT), microtubule dynamics, cyclin-dependent kinase 1 (CDK1), and cell death signaling 12 – 14 . We previously cooperated with Yashiro’s group to establish acquired PTX-resistant GC cell lines and to preliminarily link PTX resistance to enhanced drug efflux and apoptotic resistance 15 .…”

Section: Introductionmentioning

confidence: 99%

Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway

et al. 2018

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Paclitaxel (PTX) is widely used in the front-line chemotherapy for gastric cancer (GC), but resistance limits its use. Due to the lack of proper models, mechanisms underlying PTX resistance in GC were not well studied. Using established PTX-resistant GC cell sublines HGC-27R, we for the first time integrated biological traits and molecular mechanisms of PTX resistance in GC. Data revealed that PTX-resistant GC cells were characterized by microtubular disorders, an EMT phenotype, reduced responses to antimitotic drugs, and resistance to apoptosis (marked by upregulated β-tubulin III, vimentin, attenuated changes in G2/M molecules or pro-apoptotic factors in response to antimitotic drugs or apoptotic inducers, respectively). Activation of the phosphoinositide 3-kinase, the serine/threonine kinase Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase (MAPK) pathways were also observed, which might be the reason for above phenotypic alternations. In vitro data suggested that targeting these pathways were sufficient to elicit antitumor responses in PTX-resistant GC, in which the dual PI3K/mTOR inhibitor BEZ235 displayed higher therapeutic efficiency than the mTOR inhibitor everolimus or the MEK inhibitor AZD6244. Antitumor effects of BEZ235 were also confirmed in mice bearing HGC-27R tumors. Thus, these data suggest that PI3K/Akt/mTOR and MAPK pathway inhibition, especially PI3K/mTOR dual blockade, might be a promising therapeutic strategy against PTX-resistant GC.

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Decreased levels of baseline and drug-induced tubulin polymerisation are hallmarks of resistance to taxanes in ovarian cancer cells and are associated with epithelial-to-mesenchymal transition

Cited by 38 publications

References 42 publications

ROCplot.org: Validating predictive biomarkers of chemotherapy/hormonal therapy/anti‐HER2 therapy using transcriptomic data of 3,104 breast cancer patients

ROCplot.org: Validating predictive biomarkers of chemotherapy/hormonal therapy/anti‐HER2 therapy using transcriptomic data of 3,104 breast cancer patients

Molecular mechanisms of synergistic action of Ramucirumab and Paclitaxel in Gastric Cancers cell lines

Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway

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