De novo ERBB2 amplification causing intrinsic resistance to erlotinib in EGFR-L858R mutated TKI-naïve lung adenocarcinoma

Carney, Brian J.; Rangachari, Deepa; VanderLaan, Paul A.; Gowen, Kyle; Schrock, Alexa B.; Ali, Siraj M.; Costa, Daniel B.

doi:10.1016/j.lungcan.2017.08.018

Cited by 9 publications

(6 citation statements)

References 7 publications

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“…Genetic alterations regulating gene expression are frequently common in LUAD and have significant impacts on tumor phenotypes and patients’ survival. For instance, de novo ERBB2 amplification confers intrinsic resistance to erlotinib in EGFR-L858R mutated TKI-naive LUAD [44]. We also explored possible clues to KRT8 dysregulation and found that DNA low copy gain might contribute to increased KRT8 expression in LUAD (Figure 5).…”

Section: Discussionmentioning

confidence: 99%

High KRT8 Expression Independently Predicts Poor Prognosis for Lung Adenocarcinoma Patients

Xie

Dang

Guo

et al. 2019

Genes

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Keratin 8 (KRT8), a type II basic intermediate filament (IF) protein, is essential for the development and metastasis of various cancers. In this study, by analyzing RNA-seq data from the Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), we have determined the expression profile of KRT8, and assessed its prognostic significance and the possible mechanism underlying the dysregulation. Our results showed that KRT8 mRNA expression was significantly up-regulated in both LUAD and LUSC tissues compared with normal lung tissues. The high KRT8 expression group for LUAD patients significantly reduced overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate analysis revealed that KRT8 expression was an independent prognostic indicator for poor OS and RFS in LUAD patients. However, KRT8 expression had no prognostic value in terms of OS and RFS for LUSC. By exploring DNA copy number alterations (CNAs) of the KRT8 gene in LUAD, we found that DNA low copy gain (+1 and +2) was associated with elevated KRT8 mRNA expression. From the above findings, we have deduced that KRT8 is aberrantly expressed in LUAD tissues and that its expression might independently predict poor OS and RFS for LUAD patients, but not for LUSC patients.

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Section: Discussionmentioning

confidence: 99%

High KRT8 Expression Independently Predicts Poor Prognosis for Lung Adenocarcinoma Patients

Xie

Dang

Guo

et al. 2019

Genes

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“…For instance, heteroclite sulfatase 2 methylation acts as a prognostic marker for lung cancer survival (27). ERBB2 amplification results in erlotinib resistance in EGFR-L858R mutated tyrosine kinase inhibitor-naïve LUAD (28). c-Met overexpression, HER-2 gene amplification and spectrin β non-erythrocytic 1-ALK gene fusion have been reported to coexist in LUAD, and this may become a novel biomarker for cancer that is refractory to crizotinib, chemotherapy and radiotherapy, and poor prognosis (29).…”

Section: Discussionmentioning

confidence: 99%

CPSF3 is a promising prognostic biomarker and predicts recurrence of non‑small cell lung cancer

et al. 2019

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Cleavage polyadenylation specificity factor (CPSF) is the core component of the 3′-end processing complex, which determines the site of 3′-end cleavage interactions of specific sequence elements within pre-mRNAs. The present study revealed that all members of the CPSF complex were overexpressed in lung cancer tissue from The Cancer Genome Atlas (TCGA) Lung Cancer Cohort compared with normal lung tissue. Analysis of overall survival and recurrence-free survival verified that only CPSF3 was associated with prognosis and recurrence of lung adenocarcinoma (LUAD), and thus could be a promising biomarker. Additionally, receiver operating characteristic curve analysis revealed that CPSF3 may function as a diagnostic biomarker to distinguish between two histological subtypes of non-small cell lung cancer. Furthermore, analysis of the association of CPSF3 expression with clinicopathological parameters indicated that CPSF3 was associated with smoking history, tumor diameter, lymph node metastasis, clinical stage and radiation therapy in LUAD. Additionally, analysis of the DNA methylation data of the TCGA-LUAD Cohort revealed that CPSF3 DNA CpG sites (cg12057242 and cg25739938) were generally hypomethylated in LUAD compared with normal lung tissue. Correlation analysis identified the CPSF3 DNA CpG site cg25739938 to be negatively correlated with CPSF3 expression, while no correlation was identified with cg12057242. In addition, correlation analysis demonstrated that the overexpression of CPSF3 was correlated with CPSF3 DNA copy number variants (CNAs). The findings indicate that abnormal expression of CPSF3 may be caused by DNA CNAs; and DNA hypermethylation and function may be a promising diagnostic and prognostic indicator for LUAD.

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“…As an example, epidermal growth factor receptor (EGFR) mutated NSCLCs are known to harbor a multitude of cooccurring genomic events when analyzed by comprehensive genomic profiling, including mutations in: tumor protein P53 (TP53), phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), Erb-B2 receptor tyrosine kinase 2 (ERBB2), MET proto-oncogene receptor tyrosine kinase (MET) among others [18,19]. Some of these co-occurring genomic events can completely abrogate the ability to induce a response to EGFR TKI monotherapy, as in the case of high-level ERBB2 or MET amplification [20], while others have less impact on initial EGFR TKI response, as is the case of PIK3CA mutations and heterozygous PTEN mutations [18,19]. TP53 mutations in these EGFR mutated cohorts are both predictive of shorter duration of tumor responses to EGFR TKIs and also prognostic of shorter lifespans in these patients [18,19].…”

Section: Tp53 Mutations Are Predictive and Prognostic When Co-occurring With Alk Rearrangements In Lung Cancermentioning

confidence: 99%

TP53 mutations are predictive and prognostic when co-occurring with ALK rearrangements in lung cancer

Costa

2018

Annals of Oncology

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predictor of response to immune checkpoint blockade across tumour types [6, 7]. A subset of patients with gastroesophageal adenocarcinoma, who are microsatellite stable, but have high TMB, have been identified using whole exome sequencing [8]. This high mutation load population, which would fall into the large predominantly immunologically 'cold' TCGA chromosomally unstable (CIN) subgroup, also had high levels of infiltrating lymphocytes which is suggestive of an active immune response [8, 9]. These results imply that TMB could also be associated with sensitivity to immune checkpoint blockade in GC: therefore, this hypothesis warrants prospective evaluation.In summary, the negative results of JAVELIN 300 are disappointing for patients with advanced GC. To optimise the benefits of single-agent immunotherapy, work on predictive biomarkers is necessary to identify the minority of GC patients who are likely to experience prolonged disease control before treatment. For most GC patients, who have immunologically evasive tumours, development of combination therapies to overcome resistance to immune checkpoint blockade is likely to be the most successful way forward.

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De novo ERBB2 amplification causing intrinsic resistance to erlotinib in EGFR-L858R mutated TKI-naïve lung adenocarcinoma

Cited by 9 publications

References 7 publications

High KRT8 Expression Independently Predicts Poor Prognosis for Lung Adenocarcinoma Patients

High KRT8 Expression Independently Predicts Poor Prognosis for Lung Adenocarcinoma Patients

CPSF3 is a promising prognostic biomarker and predicts recurrence of non‑small cell lung cancer

TP53 mutations are predictive and prognostic when co-occurring with ALK rearrangements in lung cancer

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