Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells.

Hong Wu,Jing Liu,Zheng Zhao,Wei Zhang,Aoli Wang,Cheng Chen,Beilei Wang,Xiao-E Yan,Nathanael S Gray,Jiaxin Wu,Liang Chen,Peng Zhao,Xixiang Li,Li Wang,Juan Liu,Zi Ye,Chu Wang,Qingsong Liu,Jinhua Wang,Qianqian Wang ,Kewei Yu ,Cai‐Hong Yun ,Ellen Weisberg ,Changwei Hu

doi:10.18632/oncotarget.5182

Abstract

Through comprehensive comparison study, we found that ibrutinib, a clinically approved covalent BTK kinase inhibitor, was highly active against EGFR (L858R, del19) mutant driven NSCLC cells, but moderately active to the T790M 'gatekeeper' mutant cells and not active to wild-type EGFR NSCLC cells. Ibrutinib strongly affected EGFR mediated signaling pathways and induced apoptosis and cell cycle arrest (G0/G1) in mutant EGFR but not wt EGFR cells. However, ibrutinib only slowed down tumor progression in PC-9 and H1975 xenograft models. MEK kinase inhibitor, GSK1120212, could potentiate ibrutinib's effect against the EGFR (L858R/T790M) mutation in vitro but not in vivo. These results suggest that special drug administration might be required to achieve best clinical response in the ongoing phase I/II clinical trial with ibrutinib for NSCLC.

Highlights

Ibrutinib (PCI-32765), an irreversible BTK kinase inhibitor, has been extensively studied in a variety of hematopoietic malignancies, such as mantle cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), and acute myeloid leukemia (AML)
[13] the efficacy of chronic treatment with Gefitinib and Erlotinib is at best transient due to signaling bypass resistance mechanisms such as Her2 and MET amplification, or acquired EGFR gatekeeper T790M mutation. [14, 15] This has encouraged the development of second-generation EGFR inhibitors such as Apatinib (BIBW2992), Neratinib and Dacomitinib, which work through formation of a covalent bond with Cys797. [16,17,18] due to the lack of selectivity between the wt EGFR and mutant EGFR, these drugs showed doselimiting toxicities, which led to develop third generation EGFR (T790M) inhibitors, such as WZ4002, CO-1686 and AZD9291. [19,20,21,22]
We first screened a panel of NSCLC cancer cell lines and found that only mutant EGFR-expressing cell lines, such as H3255 (EGFR L858R, GI50: 0.11 μM), PC-9 (EGFR Del 19, GI50: 0.05 μM), and HCC827 (EGFR Del 19, GI50: 0.063 μM), are sensitive to ibrutinib treatment. (Table 1) A similar trend was observed with other EGFR inhibitors, including BIBW2992, WZ4002, CO-1686, AZD9291 and Gefitinib

Summary

Introduction

Ibrutinib (PCI-32765), an irreversible BTK kinase inhibitor, has been extensively studied in a variety of hematopoietic malignancies, such as mantle cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), and acute myeloid leukemia (AML) It was approved for the clinical treatment of MCL and CLL. Ibrutinib could be effectively combined with MEK kinase inhibitor GSK1120212 against the EGFR secondary mutant (L858/T790M) These potent anti-proliferation activities could not directly transform into PC-9 and H1975 xenografts models. These results indicated that ibrutinib might be a potential drug candidate for the EGFR (L858R, del19) mutant driven NSCLC and a useful candidate for combinatorial therapy aimed at overcoming (L858R/T790M) resistance in NSCLC. Considering the discrepancies observed between the in vitro and in vivo, special administration design might be required to achieve the best drug response in the solid NSCLC tumor

Methods

Results

Conclusion