Biomarkers for predicting response to tyrosine kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells

Li, Jixia; Lin, Bihua; Li, Xiangyong; Tang, Xudong; He, Zhiwei; Zhou, Keyuan

doi:10.3892/or.2014.3639

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…The presence of p53-responsive elements on FAS promoter region (20) and the evidence that gefitinib treatment induces an upregulation of FAS on lung cancer cells (21) further suggest a link between TKI response and TP53 status. The correlation between TP53 mutation and TKI resistance has also been demonstrated in other in vitro tumor cell models, in particular in urothelial carcinoma (32,33).…”

Section: Discussionmentioning

confidence: 66%

Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors

Canale

Petracci

Delmonte

et al. 2017

Clinical Cancer Research

227

224

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To analyze the impact of mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with-mutated non-small cell lung cancer (NSCLC). 136 -mutated NSCLC patients receiving first-line TKIs were analyzed. mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in -mutated patients compared with 88% in-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), = 0.019]. In particular, a 42% DCR was observed in patients with exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), < 0.001]. Shorter median PFS and OS were observed in patients with exon 8 mutations compared with others (4.2 vs. 12.5, = 0.058, and 16.2 vs. 32.3, = 0.114, respectively); these differences became significant in the subgroup with exon 19 deletion (4.2 vs. 16.8, < 0.001, and 7.6 vs. not reached, = 0.006, respectively), HR 6.99 (95% CI, 2.34-20.87, < 0.001) and HR 4.75 (95% CI, 1.38-16.29, = 0.013), respectively. mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in -mutated NSCLC patients, mainly those carrying exon 19 deletions..

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Section: Discussionmentioning

confidence: 66%

Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors

Canale

Petracci

Delmonte

et al. 2017

Clinical Cancer Research

227

224

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“…This approach should be effective against any HER family dimers regardless of the participating receptors. Lapatinib is a reversible HER family tyrosine kinase inhibitor (TKI) that has shown promise in pre-clinical studies in bladder cancer [ 19 ]. However, clinical trials with this drug in unselected patients with advanced bladder cancer have been disappointing [ 20, 21 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Correlates of In Vitro Responses to Dacomitinib and Afatinib in Bladder Cancer

Tamura

Wang

Veeneman

et al. 2018

BLC

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Background:The HER family of proteins (EGFR, HER2, HER3 and HER4) have long been thought to be therapeutic targets for bladder cancer, but previous clinical trials targeting these proteins have been disappointing. Second generation agents may be more effective.Objective:The aim of this study was to evaluate responses to two second-generation irreversible tyrosine kinase inhibitors, dacomitinib and afatinib, in bladder cancer cell lines.Methods:Cell lines were characterized by targeted next generation DNA sequencing, RNA sequencing, western blotting and flow cytometry. Cell survival responses to dacomitinib or afatinib were determined using (3-[4,5-dimethylthioazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT) or [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and phenazine methosylfate (PMS) cell survival assays.Results:Only two cell lines of 12 tested were sensitive to afatinib. Sensitivity to afatinib was significantly associated with mutation in either HER2 or HER3 (p < 0.05). The two cell lines sensitive to afatinib were also responsive to dacomitinib ralong with an additional 4 other cell lines out of 16 tested. No characteristic was associated with dacomitinib sensitivity. Molecular profiling demonstrated that only two genes were high in both afatinib and dacomitinib sensitive cells. Further rhigher expression of RAS pathway genes was noted for dacomitinib responsive cells.Conclusions:This study confirms that cell line screening can be useful in pre-clinical evaluation of targeted small molecule inhibitors and suggests that compounds with similar structure(s) and target(s) may have distinct sensitivity profiles. Further rcombinational targeting of additional molecularly relevant pathways may be important in enhancing responses to HER targeted agents in bladder cancer.

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“…Although it is well known that driver EGFR mutations in exons 19 and 21 predict favorable outcomes with EGFR TKIs, the effect of the passenger mutation landscape on modulating treatment outcome is unknown. Other biomarkers may influence treatment results in a negative or positive fashion, such as tumor protein 53 ( p53 ) mutation, epithelial–mesenchymal transition ( EMT ), and mitogen‐activated protein kinase 1 ( MAPK1 ) . It is important to identify genomic markers that predict not only who may respond to EGFR TKI therapy but also who may not respond to avoid unnecessary side effects and costs in those with no expected clinical benefit.…”

Section: Discussionmentioning

confidence: 99%

“…Other biomarkers may influence treatment results in a negative or positive fashion, such as tumor protein 53 (p53) mutation, epithelial-mesenchymal transition (EMT), and mitogen-activated protein kinase 1 (MAPK1). [25][26][27][28][29] It is important to identify genomic markers that predict not only who may respond to EGFR TKI therapy but also who may not respond to avoid unnecessary side effects and costs in those with no expected clinical benefit. To learn more about the molecular profile of the long-term survivors, the investigators have planned to retrieve tumor specimens from patients Original Article who did not undergo mutation analysis to analyze their genomic profile.…”

Section: Discussionmentioning

confidence: 99%

Long‐term safety and survival with gefitinib in select patients with advanced non–small cell lung cancer: Results from the US IRESSA Clinical Access Program (ICAP)

Hirsch

Sequist

Gore

et al. 2018

Cancer

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Biomarkers for predicting response to tyrosine kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells

Abstract: Abstract. The epidermal growth factor receptor (EGFR) family is reportedly overexpressed in bladder cancer, and tyrosine kinase inhibitors (TKIs) have been suggested as treatment. Gefitinib (Iressa ®

Cited by 12 publications

References 28 publications

Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors

Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors

Molecular Correlates of In Vitro Responses to Dacomitinib and Afatinib in Bladder Cancer

Long‐term safety and survival with gefitinib in select patients with advanced non–small cell lung cancer: Results from the US IRESSA Clinical Access Program (ICAP)

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