Abstract
Lung cancer continues to be the primary cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the predominant type. Dysregulation of protein translation that participates in cell proliferation is an important factor to define oncogenic processes and cancer development. The eukaryotic initiation factor 4E (eIF4E) regulates ribosomal translation of proteins from mRNA, and the mitogen-activated protein kinase interacting kinases (MNKs) is reported to be the only kinases that can phosphorylate eIF4E. Substantial previous work has proven that the MNK-eIF4E axis is usually dysregulated in many cancer types. Moreover, abnormal angiogenesis is essential for tumorigenesis and cancer progression, and vascular endothelial growth factors (VEGF) together with their receptors play multiple crucial roles in angiogenesis, especially VEGFR2. In this study, we report a novel dual MNK/VEGFR2 inhibitor named JDB153 and investigate its antitumor effects in NSCLC. JDB153 can effectively inhibit the phosphorylation of eIF4E and VEGFR2, suppress proliferation, migration and invasion, promote apoptosis, and induce cycle arrest of lung cancer cells. Importantly, JDB153 exhibits antitumor activity and synergizes with anti-PD-1 therapy and cisplatin with reliable safety. Our findings reveal the potential value of JDB153 in lung cancer as monotherapy or in combination with immunotherapy and chemotherapy, with the hope to provide a novel combinational strategy for NSCLC treatment clinically.