Lung cancer is the second most common cancers in both men and women, accounting for about 27% of all cancer deaths. Non-small cell lung cancer (NSCLC) is a major type of lung cancers, accounting for approximately 85% of all lung cancers. Roughly 10-35% of NSCLC patients have drug sensitizing mutations of the epidermal growth factor receptor (EGFR). Drugs that target EGFR provide an effective therapy for NSCLC.

Recently, a joint team in China discovered that ibrutinib was highly active against EGFR (L858R, del19) mutation driven NSCLC cells, but moderately active to the T790M ‘gatekeeper’ mutant cells and not effective against wild-type EGFR NSCLC cells.

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). Recently it was approved by FDA for the clinical treatment of MCL, CLL, and WM (Waldenstrom macroblobulinemia).

Through comprehensive comparison study, the team found that Ibrutinib strongly affected EGFR mediated signaling pathways and induced apoptosis and cell cycle arrest (G0/G1) in mutant EGFR but not wild type 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 the best clinical response in the ongoing phase I/II clinical trial with ibrutinib for NSCLC.

This work entitled “Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells” was published in the journal Oncotarget. The research group has applied for Chinese patent and international patent protection, also in collaboration with Anhui New Star Pharmaceutical Development Co. to develop this new indication by patent licenses.

The research team includes a group led by Dr. LIU Qingsong and Dr. LIU Jing from the High Magnetic Field Laboratory of the Chinese Academy of Sciences (CHMFL) and a group led by CHEN Liang from National Institute of Biological Sciences, Beijing (NIBS). WU Hong, HU Chen, WANG Beilei  made major contributions to this work.

The research was supported by the “Thousand Talent Program”, "Hundred Talent Program” of the Chinese Academy of Sciences, Anhui Province Natural Science Foundation Annual Key Program et al.

Ibrutinib anti-tumor efficacy in PC-9 and H1975 xenograft mouse models. (Image by ZHANG Wei)