Molecular correlates of gefitinib responsiveness in human bladder cancer cells

Shrader, Marissa; Pino, Maria Simona; Brown, Gordon A.; Black, Peter C.; Adam, Liana; Bar-Eli, Menahse; Dinney, Colin P.; McConkey, David J.

doi:10.1158/1535-7163.mct-06-0513

Cited by 60 publications

(46 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Loss of other epithelial markers and gain of the mesenchymal marker vimentin showed a similar but looser association. We previously showed a similar relationship with gefitinb (17), but here, we were able to establish a causal association by silencing E-cadherin expression in two sensitive urothelial carcinoma cells and thereby imparting resistance to cetuximab.…”

Section: Discussionsupporting

confidence: 65%

See 1 more Smart Citation

Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells

Black¹,

Brown²,

Inamoto³

et al. 2008

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Epidermal growth factor receptor (EGFR) is an attractive target for the treatment of urothelial carcinoma, but a clinical response can be expected in only a small proportion of patients. The aim of this study was to define molecular markers of response to cetuximab therapy in a panel of urothelial carcinoma cell lines. Experimental Design: Eleven cell lines were investigated for antiproliferative response to cetuximab based on [ 3 H]thymidine incorporation. A variety of markers, including EGFR expression, phosphorylation, and gene amplification, as well as the expression of other growth factor receptors, their ligands, and markers of epithelial-to-mesenchymal transition were investigated. Cohen's j statistic was used to estimate the agreement between response and expression of these markers. E-cadherin was silenced by small interfering RNA in two sensitive cell lines, and the effect on the response to cetuximab was measured. Results: We were able to identify a panel of relevant markers pertaining especially to alternate growth factor receptor expression and epithelial-to-mesenchymal transition that predicted response to cetuximab. The data suggested that expression of intact HER-4 (j, 1.00; P = 0.008), E-cadherin (j, 0.81; P = 0.015), and h-catenin (j, 0.81; P = 0.015) and loss of expression of platelet-derived growth factor receptor h (j, 0.57; P = 0.167) were associated with response to cetuximab therapy. Silencing E-cadherin in two sensitive cell lines reduced responsiveness to cetuximab in both (P < 0.001).Conclusions: A panel of predictive markers for cetuximab response has been established in vitro and is currently being evaluated in a prospective clinical trial of neoadjuvant EGFRtargeted therapy. Most importantly, E-cadherin seems to play a central role in modulation of EGFR response in urothelial carcinoma.

show abstract

Section: Discussionsupporting

confidence: 65%

“…A recent gene profiling study showed that resistance to erlotinib correlated closely with epithelial-to-mesenchymal transition in non -small cell lung cancer cell lines and patient tumors (16). We have recently reported similar findings with gefitinib in a series of urothelial carcinoma cell lines that we have expanded upon in this report (17).…”

supporting

confidence: 76%

Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells

Black¹,

Brown²,

Inamoto³

et al. 2008

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Two recent reports have suggested that epithelial-tomesenchymal transition (EMT) predicts in vitro sensitivity and clinical activity of erlotinib in NSCLC (17,18) whereas another report has shown a correlation between EMT and erlotinib sensitivity in pancreatic and colorectal tumor cell lines (19). Similar results have been reported for gefitinib sensitivity in cell lines from NSCLC (20), head and neck squamous cell carcinoma (20), and bladder cancer (21). Consistent with these studies, restoration of E-cadherin expression increases sensitivity to gefitinib in NSCLC (22).…”

Section: Introductionmentioning

confidence: 53%

Epithelial-to-Mesenchymal Transition and Integrin-Linked Kinase Mediate Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Hepatoma Cells

et al. 2008

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is associated with a poor prognosis due to late diagnoses and a lack of effective treatment options. Epidermal growth factor receptor (EGFR)-targeted therapies have been effective in other cancers. However, erlotinib and cetuximab have shown only modest efficacy in clinical trials of HCC. We examined epithelial-to-mesenchymal transition (EMT) as a determinant of sensitivity of HCC to EGFR inhibitors. A panel of 12 human hepatoma cell lines were classified as epithelial or mesenchymal based on their expression of E-cadherin and vimentin. The resulting classification correlated with a previous microarray analysis of human hepatoma cell lines whereby the mesenchymal cell lines were shown to have increased expression of genes involved in metastasis and invasion. Sensitivity to erlotinib, gefitinib, and cetuximab was assessed and the epithelial cell lines were found to be significantly more susceptible to all three agents. Analysis of the EGFR pathway showed that EMT status was independent of EGFR expression or downstream extracellular signal-regulated kinase activation and only the epithelial cell lines expressed ErbB3. Interestingly, mesenchymal cells resistant to EGFR inhibitors had increased AKT and signal transducer and activator of transcription-3 activation through elevated expression of integrin-linked kinase (ILK). Mesenchymal cell lines were therefore experimentally transformed with kinaseinactive ILK (KI-ILK) with a resulting decrease in ILK activity and activation of AKT. KI-ILK transformants showed increased sensitivity to EGFR inhibitors both in vitro and in an in vivo xenograft model. These data suggest that EMT predicts HCC sensitivity to EGFR-targeted therapies and that ILK is a novel target to overcome HCC resistance to EGFR inhibition.

show abstract

“…An EMT-like transition has been associated with NSCLC tumor cell, xenograft and patient insensitivity to selective EGFR tyrosine kinase inhibition [11][12][13], in part from EGFR independent activation of either or both the PI3 0 kinase or Mek-Erk pathways [14]. Similar data correlating EMT status to sensitivity to EGFR TKIs have been reported in pancreatic, CRC [14] bladder [15] and HNSCC [16] cell lines, xenografts and in patients samples [13]. The molecular determinants to alternative routes of activation of the PI3 0 kinase and/or Erk pathways, which can bypass cellular sensitivity to EGF receptor inhibitors, have been actively investigated.…”

Section: Introductionmentioning

confidence: 56%

Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy

Thomson¹,

Petti²,

Sujka-Kwok³

et al. 2008

Clin Exp Metastasis

175

147

View full text Add to dashboard Cite

NSCLC cells with a mesenchymal phenotype have shown a marked reduction in sensitivity to EGFR inhibitors, though the molecular rationale has remained obscure. Here we find that in mesenchymal-like tumor cells both tyrosine phosphorylation of EGFR, ErbB2, and ErbB3 signaling networks and expression of EGFR family ligands were decreased. While chronic activation of EGFR can promote an EMT-like transition, once having occurred EGFR family signaling was attenuated. We investigated the mechanisms by which mesenchymal-like cells bypass EGFR signaling and acquire alternative routes of proliferative and survival signaling. Mesenchymal-like NSCLC cells exhibit aberrant PDGFR and FGFR expression and autocrine signaling through these receptors can activate the MEK-ERK and PI3K pathways. Selective pharmacological inhibition of PDGFR or FGFR receptor tyrosine kinases reduced cell proliferation in mesenchymal-like but not epithelial NSCLC cell lines. A metastable, reversible EMT-like transition in the NSCLC line H358 was achieved by exogenous TGFb, which served as a model EMT system. The H358/TGFb cells showed many of the attributes of established mesenchymal-like NSCLC cells including a loss of cell-cell junctions, a loss of EGF-family ligand expression, a loss of ErbB3 expression, increased EGFRindependent Mek-Erk pathway activation and reduced sensitivity to EGFR inhibition. Notably an EMT-dependent acquisition of PDGFR, FGFR and TGFb receptors in H358/TGFbeta cells was also observed. In H358/TGFbeta cells both PDGFR and FGFR showed functional ligand stimulation of their intrinsic tyrosine kinase activities. The findings of kinase switching and acquired PDGFR and FGFR signaling suggest investigation of new inhibitor combinations to target NSCLC metastases.

show abstract

Molecular correlates of gefitinib responsiveness in human bladder cancer cells

Abstract: We characterized the effects of the small molecule epidermal growth factor receptor (EGFR) inhibitor gefiti-

Cited by 60 publications

References 36 publications

Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells

Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells

Epithelial-to-Mesenchymal Transition and Integrin-Linked Kinase Mediate Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Hepatoma Cells

Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy

Contact Info

Product

Resources

About