Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer.

Yanhua Fan,Yongnan Xu,Huaiwei Ding,Donghwa Kim,Ji-Young Hong,Duc-Hiep Bach,Sang Kook Lee

doi:10.3390/cancers11050627

Abstract

Aberrant activation of hepatocyte growth factor (HGF)/c-Met signaling pathway caused by gene amplification or mutation plays an important role in tumorigenesis. Therefore, c-Met is considered as an attractive target for cancer therapy and c-Met inhibitors have been developed with great interests. However, cancers treated with c-Met inhibitors inevitably develop resistance commonly caused by the activation of PI3K/Akt signal transduction pathway. Therefore, the combination of c-Met and PI3Kα inhibitors showed synergistic activities, especially, in c-Met hyperactivated and PIK3CA-mutated cells. In our previous study, we rationally designed and synthesized DFX117(6-(5-(2,4-difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-N-(2-morpholinoethyl) imidazo[1,2-a]pyridine-3-carboxamide) as a novel PI3Kα selective inhibitor. Herein, the antitumor activity and underlying mechanisms of DFX117 against non-small cell lung cancer (NSCLC) cells were evaluated in both in vitro and in vivo animal models. Concurrent targeted c-Met and PI3Kα by DFX117 dose-dependent inhibited the cell growth of H1975 cells (PIK3CA mutation and c-Met amplification) and A549 cells (KRAS mutation). DFX117 subsequently induced G0/G1 cell cycle arrest and apoptosis. These data highlight the significant potential of DFX117 as a feasible and efficacious agent for the treatment of NSCLC patients.

Highlights

Introduction cMet receptor tyrosine kinase (RTK), activated by its ligand hepatocyte growth factor (HGF), is frequently hyperactivated, amplified or mutated in many human cancers including lung cancer [1,2,3,4].The binding of HGF with c-Met leads to c-Met autophosphorylation at tyrosine residues Y1234 andY1235 within the activation loop of the kinase domain and eventually phosphorylates at tyrosinesY1349 and Y1356 to activate c-Met-mediated signaling pathway
The present study revealed that DFX117 is a potent c-Met tyrosine kinase inhibitor
Our previous study revealed that DFX117 is a selective PI3Kα inhibitor with an IC50 value of

Summary

Introduction

Met receptor tyrosine kinase (RTK), activated by its ligand hepatocyte growth factor (HGF), is frequently hyperactivated, amplified or mutated in many human cancers including lung cancer [1,2,3,4]. Y1349 and Y1356 to activate c-Met-mediated signaling pathway. Cancers 2019, 11, 627 resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) [5,6,7]. EGFR inhibitors on EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells harboring acquired c-Met gene amplification [8,9,10]. C-Met is considered as an attractive target biomarker for cancer therapy, for EGFR-TKI resistant cancer. A diverse class of c-Met inhibitors has been developed as anticancer agents for c-Met-driven tumors [11,12,13]

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