EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype

Rebouissou, Sandra; Bernard‐Pierrot, Isabelle; Reyniès, Aurélien de; Lepage, May‐Linda; Krucker, Clémentine; Chapeaublanc, Élodie; Hérault, Aurélie; Kamoun, Aurélie; Caillault, Aurélie; Letouzé, Éric; Elarouci, Nabila; Neuzillet, Y.; Denoux, Yves; Molinié, Vincent; Vordos, Dimitri; Laplanche, Agnès; Maillé, Pascale; Soyeux, Pascale; Ofualuka, Karina; Reyal, Fabien; Biton, Anne; Sibony, Mathilde; Paolettí, Xavier; Southgate, Jennifer; Benhamou, Simone; Lebrét, Thierry; Allory, Yves; Radvanyi, François

doi:10.1126/scitranslmed.3008970

Cited by 328 publications

(351 citation statements)

References 39 publications

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“…In agreement with this idea, CCNB1 and CCNE2, whose actions are CDKN2A-independent, are both overexpressed in basal-like bladder tumors presenting an activation of EGFR target genes (48). Mutual exclusivity of FGFR3 and TP53 mutations has been reported for all tumors rather than tumors separated by stage (19).…”

Section: Data Interpretation Using the Modelsupporting

confidence: 56%

“…In the CIT dataset, EGFR-amplified tumors (which belong to the basal-like bladder tumor subtype; ref. 48) do not seem to lose CDKN2A more frequently than FGFR3-mutated tumors, and, more surprisingly, CDKN2A expression is increased when compared with the nonbasal tumors. This suggests two things: (i) CDKN2A may compensate transcriptionally for the loss of RB activation in these tumors; and (ii) in bladder, FGFR3 activates the cell cycle through CDK4/6 (CDKN2A-dependent), whereas EGFR activates the cell cycle in a CDKN2A-independent NOTE: þþ, increase higher than 10% (in absence of DNA damage); þ, an increase higher than 5%; ÀÀ, decrease higher than 10% (in absence of DNA damage); À, a decrease higher than 5%.…”

Section: Data Interpretation Using the Modelmentioning

confidence: 94%

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A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

et al. 2015

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Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer.

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Section: Data Interpretation Using the Modelsupporting

confidence: 56%

Section: Data Interpretation Using the Modelmentioning

confidence: 94%

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

et al. 2015

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“…Activation of the EGFR pathway has been identified in basal-type MIBC and it was shown that cell lines with this signature were sensitive to EGFR inhibition 198 .…”

Section: Beyond the 'Two Pathway' Modelmentioning

confidence: 99%

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

2014

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Correspondence to M.A.K. m.a.knowles@leeds.ac.uk 2 Preface Urothelial carcinoma of the bladder comprises two long-recognised disease entities with distinct molecular features and clinical outcome. Low-grade, non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that cut across conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalised therapy.Bladder cancer is the most common cancer of the urinary tract with approximately 380,000 new cases and 150,000 deaths per year worldwide 1 . It ranks fifth among cancers in men in Western countries.Epidemiological studies identify a range of environmental risk factors, many of which reflect exposure to excreted carcinogenic molecules (BOX 1). Recent genome-wide association studies have also identified germline variants that contribute to risk 2 .In Europe and North America, more than 90% of bladder cancers are urothelial carcinoma. These tumours are staged using the Tumour Nodes Metastasis (TNM) system 3 , which describes the extent of invasion (Tis-T4), and graded according to their cellular characteristics. Two classification systems are in current use 4, 5 .At diagnosis the majority of bladder cancers (~ 60%) are non-muscle-invasive (NMIBC) (stage Ta) NMIBCs frequently recur (50-70%) but infrequently progress to invasion (10-15%) 6 and five-year survival is ~90%. These patients are monitored by cystoscopy and may have multiple resections over many years.Improved monitoring is needed, ideally via urine analysis, which could reduce the morbidity and costs associated with cystoscopy. Although risk tables provide a prognostic tool 7 , no molecular biomarkers accurately predict disease progression. For these patients, localised therapies to remove residual neoplastic and preneoplastic cells post-resection may have major impacts on both quality of life and in health economic terms. MIBCs (>stage T2) have less favourable prognosis with five-year survival <50% and common progression to metastasis (BOX1). Treatment has not advanced for several decades and new approaches to systemic therapy are needed 8 .Improved treatment requires detailed understanding of urothelial carcinoma pathogenesis and molecular biology. A model has evolved, taking into account both histopathological and molecular features. This socalled 'two-pathway' model proposes that papillary NMIBC develops via epithelial hyperplasia and recruitment of a branching vasculature. MIBCs are proposed to develop via flat dysplasia and carcinoma in situ (CIS). The molecular characteristics of MIBC and NMIBC are highly distinct (Tables 1 and 2). Whilst 3 m...

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“…In addition, a subgroup of muscle-invasive bladder carcinoma displaying a basal-like phenotype is sensitive to EGFR inhibitor erlotinib (5). However, the underlying mechanisms remained unknown.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Wang

Chu

et al. 2017

Clinical Cancer Research

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Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy.Experimental Design: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity.Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel.Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201.

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EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype

Cited by 328 publications

References 39 publications

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

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