Erdafitinib Inhibits Tumorigenesis of Human Lung Adenocarcinoma A549 by Inducing S-Phase Cell-Cycle Arrest as a CDK2 Inhibitor

Abstract

Lung adenocarcinoma (LADC) is the most prevalent lung cancer sub-type, and targeted therapy developed in recent years has made progress in its treatment. Erdafitinib, a potent and selective pan-FGFR tyrosine kinase inhibitor, has been confirmed to be effective for the treatment of LADC; however, the molecular mechanism responsible for this effect is unclear. The in vitro study showed that erdafitinib exhibited an outstanding anti-cancer activity in human LADC cell line A549 by inducing S-phase cell-cycle arrest and cell apoptosis. The mechanistic study based on the transcriptomic data revealed that erdafitinib exerted its anti-cancer effect by affecting the cell cycle-related pathway, and CDK2 was the regulatory target of this drug. In addition, CDK2 overexpression significantly attenuated the anti-cancer effect of erdafitinib by affecting the transcriptional activity and expression of E2F1, as well as the expression of CDK1. The in vivo study showed that erdafitinib presented an obvious anti-cancer effect in the A549 xenograft mice model, which was accompanied by the reduced expression of CDK2. Thus, this study demonstrates the anti-cancer effect of erdafitinib against LADC for the first time based on in vitro and in vivo models, whose activity is achieved by targeting CDK2 and regulating downstream E2F1-CDK1 signaling. This study may be helpful for expanding the clinical application of erdafitinib in treating LADC.

New spiro-indeno[1,2- b ]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights

“…Accordingly, we started from spirooxindole I ( Figure 1 ) being a privileged framework. The oxindole fragment was replaced by quinoxaline; the pharmacophoric core of erdafitinib that was recently found to inhibit tumorigenesis of NSCLC A549 cells via CDK2 inhibition 28 . With that, a pioneer study probing the effect of indeno ring substitution pattern and fusion to a heterocyclic motif on CDK2 inhibition potential 29 directed our design rationale to assemble indeno[1,2- b ]quinoxaline-based spiro compounds.…”