scholarly journals Clinical significance of ERBB2 exon 16 skipping: analysis of a real-world retrospective observational cohort study

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e000985
Author(s):  
Lei Shi ◽  
Caihua Xu ◽  
Yutong Ma ◽  
Qiuxiang Ou ◽  
Xue Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Rna Sequencing ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Chinese Patients ◽  
Transcriptional Level ◽  
Driver Genes ◽  
Large Patient ◽  
Tki Resistance ◽  
Oncogenic Driver

BackgroundERBB2 exon 16 skipping is an alternatively spliced isoform of ERBB2, which was reported to lead to oncogenic activation of ERBB2 and could potentially cause tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) in case studies. In this study, we aimed to evaluate the frequency of ERBB2 exon 16 skipping in a large patient cohort and its function in cancer development.MethodsA total of 38 680 Chinese patients with cancer whose tumour specimens and/or circulating cell-free DNA underwent targeted nextgeneration sequencing of cancer-related genes were retrospectively reviewed. Clinicopathological features and treatment history of patients harbouring ERBB2 exon 16 skipping were evaluated. RNA-sequencing was performed to validate the presence of exon 16 skipping in ERBB2 at the transcriptional level.ResultsERBB2 exon 16 skipping is rare and was identified in a total of 18 patients (0.046% of total patients), including 12 lung cancers, which were caused by large fragment deletion spanning the whole or partial region of exon 16 (13/18, 72.2%) and/or splice site variants (6/18, 33.3%). The majority of these variants have not been previously reported and three of them were confirmed by RNA-sequencing. Among the 12 patients with lung cancer, 9 had coexisting activating EGFR mutations (exon 19 deletions or L858R) and received prior-treatment with epidermal growth factor receptor TKIs. Further analysis of matched pre-treatment and post-treatment samples in three EGFR-mutated NSCLC patients confirmed that ERBB2 exon 16 skipping was newly acquired on resistance to TKI therapies. In 6 out of 18 patients, including colorectal, gastric and ovarian cancers, there were no mutations in known cancer driver genes detected, indicating that ERBB2 exon 16 skipping might be the oncogenic driver in these patients.ConclusionsOur data suggest that ERBB2 exon 16 skipping is another mechanism of TKI resistance in EGFR-mutated patients with lung cancer, in addition to its role of being an oncogenic driver in other solid malignancies.

scholarly journals Inhibition of miR-185-3p Confers Erlotinib Resistance Through Upregulation of PFKL/MET in Lung Cancers

2021 ◽  
Vol 9 ◽  
Author(s):  
Ke Li ◽  
Xinling Zhu ◽  
Conghu Yuan
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Lung Cancer Cells ◽  
Cell Counting ◽  
Luciferase Assay ◽  
Lung Cancers ◽  
Tki Resistance ◽  
Egfr Tki

Erlotinib (ER), as an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has a significant therapeutic effect in lung cancers. However, EGFR TKI resistance inevitably occurs after treatment for approximately 12 months, which weakens its antitumor effect. Here, we identified miR-185-3p as a significantly downregulated microRNA responsible for acquired EGFR TKI resistance in cells and patients with lung cancer. qRT-PCR and Western Blot were performed to determine the relative expression of miR-185-3p in ER-resistant tumor tissues and cells. The viability and apoptosis of lung cancer cells were evaluated by Cell Counting Kit-8 (CCK8) assay and flow cytometry, respectively. The binding between miR-185-3p and liver-type phosphofructokinase (PFKL) was verified by dual luciferase assay. It was found that overexpression of miR-185-3p conferred ER sensitivity in lung cancer cell lines. MiR-185-3p was downregulated in ER-resistant lung cancer cells (H1299/ER and A549/ER). MiR-185-3p inhibited proliferation and induced cell apoptosis in ER-resistant cells. Mechanistically, miR-185-3p downregulation contributed to ER resistance through upregulating the PFKL. Moreover, Mesenchymal to epithelial transition (MET) oncoprotein promoted EGFR-TKI resistance by regulating miR-185-3p and PFKL. These findings revealed a novel mechanism in which downregulation of miR-185-3p may induce overexpression of PFKL and MET and confer ER resistance in lung cells. Combination of PFKL/MET inhibitors and EGFR TKIs could be a rational therapeutic approach for lung cancer patients with EGFR mutation.

scholarly journals RNA Sequencing in Comparison to Immunohistochemistry for Measuring Cancer Biomarkers in Breast Cancer and Lung Cancer Specimens

Biomedicines ◽  
2020 ◽  
Vol 8 (5) ◽  
pp. 114
Author(s):  
Maxim Sorokin ◽  
Kirill Ignatev ◽  
Elena Poddubskaya ◽  
Uliana Vladimirova ◽  
Nurshat Gaifullin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Rna Sequencing ◽  
Expression Profiles ◽  
Correlation Study ◽  
Cancer Tissue ◽  
Transcriptional Level ◽  
Tissue Samples ◽  
Protein Levels ◽  
Formalin Fixed Paraffin Embedded

RNA sequencing is considered the gold standard for high-throughput profiling of gene expression at the transcriptional level. Its increasing importance in cancer research and molecular diagnostics is reflected in the growing number of its mentions in scientific literature and clinical trial reports. However, the use of different reagents and protocols for RNA sequencing often produces incompatible results. Recently, we published the Oncobox Atlas of RNA sequencing profiles for normal human tissues obtained from healthy donors killed in road accidents. This is a database of molecular profiles obtained using uniform protocol and reagents settings that can be broadly used in biomedicine for data normalization in pathology, including cancer. Here, we publish new original 39 breast cancer (BC) and 19 lung cancer (LC) RNA sequencing profiles obtained for formalin-fixed paraffin-embedded (FFPE) tissue samples, fully compatible with the Oncobox Atlas. We performed the first correlation study of RNA sequencing and immunohistochemistry-measured expression profiles for the clinically actionable biomarker genes in FFPE cancer tissue samples. We demonstrated high (Spearman’s rho 0.65–0.798) and statistically significant (p < 0.00004) correlations between the RNA sequencing (Oncobox protocol) and immunohistochemical measurements for HER2/ERBB2, ER/ESR1 and PGR genes in BC, and for PDL1 gene in LC; AUC: 0.963 for HER2, 0.921 for ESR1, 0.912 for PGR, and 0.922 for PDL1. To our knowledge, this is the first validation that total RNA sequencing of archived FFPE materials provides a reliable estimation of marker protein levels. These results show that in the future, RNA sequencing can complement immunohistochemistry for reliable measurements of the expression biomarkers in FFPE cancer samples.

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