Ibrutinib reverses IL-6-induced osimertinib resistance through inhibition of Laminin α5/FAK signaling.

Abstract

Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line standard-of-care for EGFR-mutant non-small cell lung cancer (NSCLC) patients, while acquired drug resistance will inevitably occur. Interleukin-6 (IL-6) is a keystone cytokine in inflammation and cancer, while its role in osimertinib efficacy was unknown. Here we show that clinically, plasma IL-6 level predicts osimertinib efficacy in EGFR mutant NSCLC patients. Highly increased IL-6 levels are found in patients with acquired resistance to osimertinib. Addition of IL-6 or exogenous overexpression of IL-6 directly induces osimertinib resistance. Proteomics reveals LAMA5 (Laminin α5) and PTK2, protein tyrosine kinase 2, also called focal adhesion kinase (FAK), are activated in osimertinib-resistant cells, and siRNA knockdown of LAMA5 or PTK2 reverses IL-6-mediated osimertinib resistance. Next, using a large-scale compound screening, we identify ibrutinib as a potent inhibitor of IL-6 and Laminin α5/FAK signaling, which shows synergy with osimertinib in osimertinib-resistant cells with high IL-6 levels, but not in those with low IL-6 levels. In vivo, this combination inhibits tumor growth of xenografts bearing osimertinib-resistant tumors. Taken together, we conclude that Laminin α5/FAK signaling is responsible for IL-6-induced osimertinib resistance, which could be reversed by combination of ibrutinib and osimertinib.

• Authors: Li Li, Zhujun Li, Conghua Lu, Jianghua Li, Kejun Zhang, Caiyu Lin, Xiaolin Tang, Zhulin Liu, Yimin Zhang, Rui Han, Yubo Wang, Mingxia Feng, Yuan Zhuang, Chen Hu, Yong He
• Journal: Communications biology (Commun Biol) Vol. 5 Issue 1 Pg. 155 (02 23 2022) ISSN: 2399-3642 [Electronic] England
• PMID: 35197546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Acrylamides
• Aniline Compounds
• IL6 protein, human
• Interleukin-6
• Laminin
• Piperidines
• laminin alpha5
• ibrutinib
• osimertinib
• ErbB Receptors
• Focal Adhesion Kinase 1
• Focal Adhesion Protein-Tyrosine Kinases
• PTK2 protein, human
• Adenine

Topics

• Acrylamides
• Adenine (analogs & derivatives)
• Aniline Compounds (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Drug Resistance, Neoplasm
• ErbB Receptors (genetics, metabolism)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Focal Adhesion Protein-Tyrosine Kinases (genetics)
• Humans
• Interleukin-6 (blood)
• Laminin (metabolism)
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mutation
• Piperidines