Epidermal Growth Factor Receptor Positive Lung Research Articles

Immunohistochemical analysis of epidermal growth factor receptor as a predictive biomarker in lung adenocarcinoma – A cross-sectional study of 33 cases on computed tomography-guided core needle biopsy specimens

Background: Lung cancer is the second most common cause of cancer in all ages and both genders and is the leading cause of cancer death. Two major groups of lung cancers are – small cell lung carcinoma (SCLC) and non-SCLC (NSCLC). Due to discovery of driver mutation such as epidermal growth factor receptor (EGFR) mutation in NSCLC, the paradigm of lung cancer therapy has shifted from cytotoxic platinum based therapy to tyrosine kinase inhibitor (TKI) therapy. In this study, we have analyzed EGFR expression in NSCLC by immunohistochemistry (IHC) and studied the response to TKI therapy in terms of progression free survival (PFS) and overall survival (OS). Aims and Objectives: In this study, we have retrospectively analyzed the EGFR overexpression in adenocarcinoma of lung in core needle biopsy (CNB) specimen by IHC analysis and correlated with the therapeutic response and survival rate (OS and PFS) in lung carcinoma patients. Materials and Methods: We have analyzed retrospectively EGFR expression in lung adenocarcinoma cases (computed tomography-guided CNB specimen) by IHC. In our study, we have used monoclonal primary antibodies against two most common EGFR mutations, that is, L858R point mutation and E 746–A 750 deletion. Results: Out of 33 cases, EGFR expression was seen in 28 cases. For EGFR expression assessment by IHC, both cytoplasmic and/or membranous staining taken into consideration. EGFR positivity was interpreted only when >10% tumor cells having 2+ or more intensely staining pattern. The response to TKI therapy in terms of PFS and OS was also studied. Conclusion: IHC analysis of EGFR mutation using specific antibodies has extremely high specificity with good sensitivity. Use of targeted therapy in the form of TKI in EGFR positive lung adenocarcinoma has high response rate and long duration of survival (PFS and OS) with acceptable toxicity profile in contrast to the conventional therapy.

And Finally: Matters of Life and Death

And Finally: Matters of Life and Death

Construction of a circRNA-miRNA-mRNA Regulated Pathway Involved in EGFR-TKI Lung Adenocarcinoma Resistance.

Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors are widely used for lung epidermal growth factor receptor-positive lung adenocarcinomas, but acquired resistance is inevitable. Although non-coding RNAs, such as circular RNA and microRNA, are known to play vital roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance, comprehensive analysis is lacking. Thus, this study aimed to explore the circular RNA-microRNA-messenger RNA regulatory network involved in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. Methods: To identify differentially expressed genes between the epidermal growth factor receptor-tyrosine kinase inhibitor sensitive cell line PC9 and resistant cell line PC9/ epidermal growth factor receptor-tyrosine kinase inhibitor resistance(PC9/ER), circular RNA, microRNA and messenger RNA microarrays were performed. Candidates were then identified to construct a circular RNA-microRNA-messenger RNA network using bioinformatics. Additionally, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to evaluate the network messenger RNA, setting up a protein-protein interaction network for hub-gene identification. Afterwards, RNA immunoprecipitation was performed to enrich microRNA, and quantitative real-time PCR was used to estimated gene expression levels. Results: In total, 603, 377, and 1863 differentially expressed circular RNA, microRNA, messenger RNAs, respectively, were identified using microarray analysis, constructing a circular RNA-microRNA-messenger RNA network containing 18 circular RNAs, 17 microRNAs and 175 messenger RNAs. Moreover, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the most enriched biological process terms and pathways were related to epidermal growth factor receptor-tyrosine kinase inhibitor resistance, including Wnt and Hippo signaling pathways. Based on the competing endogenous RNA and protein-protein interaction network, circ-0007312 was showed to interact with miR-764 and both circ-0003748 and circ-0001398 were shown to interact with miR-628; both these microRNAs targeted MAPK1. Furthermore, circ-0007312, circ-0003748, circ-0001398, and MAPK1 were up-regulated, whereas miR-764 and miR-628 were downregulated in PC9/ER cells as compared to parental PC9 cells. We also found that circ-0007312 and miR-764 were positively expressed in plasma. Conclusions: Our original study associated with mechanism of target therapy in lung cancer provided a systematic and comprehensive regulation of circular RNA, microRNA and messenger RNA in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. It was found that circ-0007312- miR-764-MAPK1, circ-0003748-miR-628-MAPK1, and circ-0001398-miR-628-MAPK1 axis may play key roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance.

Is age just a number for patients with epidermal growth factor receptor-positive lung cancer?

Is age just a number for patients with epidermal growth factor receptor-positive lung cancer?

Abstract 1875A: Preclinical proof of concept for the first Nanocyclix TKI-PET radiotracer targeting activated EGFR positive lung tumors

Abstract Background: IMAkinib® program is an innovative approach, based on Nanocyclix® chemistry technology, which aims to develop new Tyrosine Kinase Inhibitors (TKIs) radiotracers used for Positron Emission Tomography (PET). The epidermal growth factor receptor (EGFR) is an established target for the treatment of advanced non-small cell lung cancer (NSCLC). Gefitinib (Iressa®), erlotinib (Tarceva®) and afatinib (Giotrif®), TKIs targeting EGFR have already been approved for treatment of advanced non-small cell lung cancer (NSCLC). Unfortunately, the majority of patients develop a resistance to the TKI, which is for most of them (> 50%) related to an acquired T790M mutation of EGFR. TKI PET-imaging can provide a tool to determine and predict the activity of EGFR and the responsiveness to EGFR TKI. Methods: New compound ODS2004436 was characterized in vitro for its activity and metabolism. After radiolabeling with [18F], the compound was evaluated in vivo in three clinically relevant lung cancer cell lines (NCI-H441 – EGFR_wild-type (WT); NCI-H3255 - EGFR_L858R; NCI-H1975 – EGFR_L858R/T790M) xenografted in nude rats. Results: The biochemical and cellular profiles were comparable to gefitinib on EGFR_WT and activated EGFR_L858R mutant. The cellular activity was in the nanomolar range (5 ± 2 nM) on NCI-H3255 and weak on NCI-H441 (42 ± 27 µM) suggesting that our compound might inhibit to a lesser extent non activated WT-EGFR. We observed a better biochemical inhibition (254 nM vs 1350 nM) and cellular activity on NCI-H1975, the EGFR double mutant (4.8 ± 0.7 µM vs 18 ± 8.7 µM) of ODS2004436 compared to gefitinib. These data suggest that our compound is suitable to bind in vivo activated EGFR. In vitro binding experiments showed that [18F]-ODS2004436 specifically bound to patient tumor samples expressing EGFR. The in vivo experiments in rats showed that [18F]-ODS2004436 was rapidly cleared from the blood. Nevertheless the tumor uptake is stable overtime (up to 180 min) with a mean tumor/muscle ratio > 4 in NCI-H3255 and > 2 in NCI-H1975 at 90 min instead no specific binding was observed in the WT tumor, NCI-H441. Moreover, we observed a good correlation between the radiotracer uptake in the tumors and pEGFR immunostaining, suggesting that [18F]-ODS2004436 is a good biomarker of activated EGFR, regardless of the mutation. Conclusions: Based on this study, we proved in vivo that [18F]-ODS2004436 binds selectively to activated EGFR, and is a good candidate to evaluate the EGFR activity in NLCSC using PET imaging. Clinical evaluation of this novel radiotracer is ongoing (first in-man phase 0/I clinical trial NCT02847377). Citation Format: Philippe Genne, Cyril Berthet, Olivier Raguin, Sylvie Chalon, Xavier Tizon, Sophie Serriere, Peggy Provent, Marc Hillairet de Boisferon, Johnny Vercouillie, Céline Mothes, Fabienne Gourand, Louisa BARRE, Denis Guilloteau, Pétra Blom, Jan Hoflack. Preclinical proof of concept for the first Nanocyclix TKI-PET radiotracer targeting activated EGFR positive lung tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1875A. doi:10.1158/1538-7445.AM2017-1875A