EphB4 as a Novel Target for the EGFR-Independent Suppressive Effects of Osimertinib on Cell Cycle Progression in Non-Small Cell Lung Cancer.

Ren Nanamiya,Jiro Abe,Hironobu Sasano,Teeranut Asavasupreechar,Ikuro Sato,Yasuhiro Miki,Chihiro Inoue,Ryoko Saito-Koyama

doi:10.3390/ijms22168522

Abstract

Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.

Highlights

Lung cancer is one of the most common causes of cancer-related deaths worldwide [1].In lung adenocarcinoma, the most frequent histological subtype among non-small cell lung cancer (NSCLC), molecular-targeted therapy for various driver mutations such as the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)have been recently used in clinical settings to provide better clinical outcomes
We examined the cell viability of four cell lines (H1975, PC9, A549, and LK2) after treatment with EGFR-tyrosine kinase inhibitors (TKIs) for 72 h
We examined the association between osimertinib and total ephrin receptor B4 (EphB4) in NSCLC using four EGFR knocked down cell lines: A549, LK2, PC9, and H1975

Summary

Introduction

Lung cancer is one of the most common causes of cancer-related deaths worldwide [1].In lung adenocarcinoma, the most frequent histological subtype among non-small cell lung cancer (NSCLC), molecular-targeted therapy for various driver mutations such as the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)have been recently used in clinical settings to provide better clinical outcomes. Among the therapeutic relevant mutations, EGFR mutations account for approximately 50% of lung adenocarcinoma cases in East Asia [2], and EGFR-tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib have been used as molecular-targeted therapeutic agents for patients with EGFR mutation-positive lung adenocarcinoma. These agents have contributed to the improvement of clinical outcomes [3,4,5,6,7,8], but therapeutic resistance is inevitable within several months of their administration [9]. Osimertinib is becoming the gold standard for the treatment of patients with EGFR mutation-positive lung adenocarcinoma, and its use is expected to expand in near future

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