Molecular characteristics of non-small cell lung cancer with reduced CHFR expression in The Cancer Genome Atlas (TCGA) project

Brodie, Seth A.; Li, Ge; Brandes, Johann C.

doi:10.1016/j.rmed.2014.11.004

Cited by 9 publications

(9 citation statements)

References 11 publications

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“…We have previously reported that advanced lung cancer patients with CHFR deficient lung cancers have remarkably high clinical benefits rates following taxane-based first line chemotherapy (81% vs 48%, p = 0.03) and significantly improved overall-survival (HR = 0.24; 95% CI, 0.1–0.58%; P = 0.002) suggesting that in this setting, taxanes can be considered targeted therapy against CHFR-low expressing tumors [ 6 ]. CHFR expression is reduced in tumors that are driven by EGFR mutations in exons 19 or 21, but EGFR mutations do not account for all cases of reduced CHFR expression [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Small molecule inhibition of the CHFR-PARP1 interaction as novel approach to overcome intrinsic taxane resistance in cancer

Brodie

Harvey

et al. 2015

Oncotarget

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The mitotic checkpoint protein CHFR has emerged as a major mediator of taxane resistance in cancer. Here we show that CHFR's PAR-binding zinc finger domain (PBZ) mediates a protein interaction with poly-ADP ribosylated PARP1 leading to stabilization of CHFR. Disruption of the CHFR-PARP1 interaction through either PARP1 shRNA-mediated knockdown or overexpression of a PBZ domain peptide induces loss of CHFR protein expression. In an attempt to exploit this observation therapeutically, and to develop compounds with synthetic lethality in combination with taxanes, we performed a high-throughput computational screen of 5,256,508 chemical structures against the published crystal structure of the CHFR PBZ domain to identify candidate small molecule CHFR protein-protein interaction inhibitors. The 10 compounds with the best docking scores (< −9.7) were used for further in vitro testing. One lead compound in particular, termed ‘A3’, completely disrupted the protein-protein interaction between CHFR and PARP1, resulting in the inhibition of mitotic checkpoint function, and led to therapeutic synergy with docetaxel in cell viability and colony formation assays. In mouse xenografts, i.p. administration of ‘A3’ led to a significant reduction in nuclear CHFR protein expression with a maximal effect 4 hours after administration, confirming relevant pharmacodynamics following the peak of ‘A3’ plasma concentration in vivo. Furthermore, combination of A3 and taxane led to significant reduction of implanted tumor size without increase in hematological, hepatic or renal toxicity. These findings provide a proof-of-principle that small molecule inhibition of CHFR PBZ domain interaction is a novel potential therapeutic approach to increase the efficacy of taxane-based chemotherapy in cancer.

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Section: Introductionmentioning

confidence: 99%

Small molecule inhibition of the CHFR-PARP1 interaction as novel approach to overcome intrinsic taxane resistance in cancer

Brodie

Harvey

et al. 2015

Oncotarget

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“…In the past years, a series of secondary analyses using data in TCGA have identified some promising and potential biomarkers in lung cancer. For example, checkpoint with fork-head and ringfinger domains ( CHFR ) expression is a valuable predictor for response to taxane-based first-line chemotherapy in NSCLC [ 18 ]. One recent study using data in TCGA found that CHFR expression was associated with epidermal growth factor receptor ( EGFR ) exon19/21 mutations in adenocarcinoma and male gender in squamous cell carcinoma [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…For example, checkpoint with fork-head and ringfinger domains ( CHFR ) expression is a valuable predictor for response to taxane-based first-line chemotherapy in NSCLC [ 18 ]. One recent study using data in TCGA found that CHFR expression was associated with epidermal growth factor receptor ( EGFR ) exon19/21 mutations in adenocarcinoma and male gender in squamous cell carcinoma [ 18 ]. Another recent study assessed the prognostic value of epithelial cell transforming 2 ( ECT2 ) in NSCLC and observed that increased ECT2 expression might independently predict poor OS and RFS in LUAD, but not in lung squamous cell carcinoma [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Aberrant S100A16 expression might be an independent prognostic indicator of unfavorable survival in non-small cell lung adenocarcinoma

2018

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S100A16 is a conserved member of the S100 protein family in mammals. Its upregulation was observed in many tumors and is related to malignant transformation. In this study, we explored the independent prognostic value of S100A16 in terms of overall survival (OS) and recurrence-free survival (RFS) by performing a retrospective study, using data in The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD). Besides, by using deep sequencing data in TCGA-LUAD, we also explored the association between S100A16 expression and its DNA methylation and copy number alterations (CNAs). Results showed that the primary LUAD tissues (N = 514) had significantly elevated S100A16 expression compared with the normal lung tissues (N = 59). Based on OS data of 502 primary LUAD cases, we found that high S100A16 expression was correlated with inferior OS. The following univariate and multivariate analysis confirmed that increased S100A16 expression was an independent prognostic indicator of unfavorable OS (HR: 1.197, 95%CI: 1.050–1.364, p = 0.007) and RFS (HR: 1.206, 95%CI: 1.045–1.393, p = 0.011). By examining the DNA methylation data in TCGA-LUAD, we found that some S100A16 DNA CpG sites were generally hypermethylated in normal tissues, but not in LUAD tissues. Regression analysis identified a moderately negative correlation between S100A16 expression and its DNA methylation. In comparison, although DNA amplification (+1/+2) was frequent (378/511, 74%) in LUAD patients, it was not associated with increased S100A16 expression. Based on findings above, we infer that aberrant S100A16 expression might be modulated by its DNA hypomethylation and serves as an independent prognostic indicator of unfavorable OS and RFS in LUAD.

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“…In addition, prior studies demonstrated that the loss of several suppressor genes such as Wnt inhibitory factor-1 ( Wif1 ) [ 32 ], Phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) [ 33 ] and TP53 [ 34 – 36 ] occurred more frequently in SSC than in ADC. P53 mutations were the most common one in SCC, occurring at 50% of cases, however there was no relationship between CHFR expression and p53 mutation [ 37 ], indicating CHFR may contribute the carcinogenesis of SCC independently. Interestingly, present data showed that CHFR promoter methylation was associated with smoking behavior which is a risk factor for the development of SSC [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological significance of CHFR methylation in non-small cell lung cancer: a systematic review and meta-analysis

Wang

Wei

et al. 2017

Oncotarget

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Checkpoint with Forkhead-associated and Ring finger domains (CHFR) is a G2/M checkpoint and tumor-suppressor gene. Recent publications showed the correlation of CHFR promoter methylation with clinicopathological significance of non-small cell lung cancer (NSCLC), however, the results remain inconsistent. The aim of this study is to investigate the Clinicopathological significance of CHFR promoter methylation in NSCLC with a meta-analysis. A total of nine studies were included in the meta-analysis that 816 patients were involved. Our data indicated that the frequency of CHFR promoter methylation was higher in NSCLC than in normal lung tissue, Odd Ratios (OR) was 9.92 with 95% corresponding confidence interval (CI) 2.17–45.23, p = 0.003. Further subgroup analysis revealed that CHFR promoter was more frequently methylated in squamous cell carcinoma (SCC) than in adenocarcinoma (ADC), OR was 4.46 with 95% CI 1.65–12.05, p = 0.003, suggesting the mechanism of SCC pathogenesis is different from ADC. Notably, CHFR promoter methylation was correlated with smoking behavior in NSCLC. In conclusion, CHFR could be a biomarker for diagnosis of NSCLC, and a promising drug target for development of gene therapy in SCC. CHFR promoter methylation is potentially associated with poor overall survival, additional studies need to be carried out for confirmation in future.

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Molecular characteristics of non-small cell lung cancer with reduced CHFR expression in The Cancer Genome Atlas (TCGA) project

Cited by 9 publications

References 11 publications

Small molecule inhibition of the CHFR-PARP1 interaction as novel approach to overcome intrinsic taxane resistance in cancer

Small molecule inhibition of the CHFR-PARP1 interaction as novel approach to overcome intrinsic taxane resistance in cancer

Aberrant S100A16 expression might be an independent prognostic indicator of unfavorable survival in non-small cell lung adenocarcinoma

Clinicopathological significance of CHFR methylation in non-small cell lung cancer: a systematic review and meta-analysis

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