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

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

  • Commun Biol. 2022 Feb 23;5(1):155. doi: 10.1038/s42003-022-03111-7.
Li Li  # 1 Zhujun Li  # 2 Conghua Lu  # 2 Jianghua Li 2 Kejun Zhang 3 Caiyu Lin 2 Xiaolin Tang 2 Zhulin Liu 2 Yimin Zhang 2 Rui Han 2 Yubo Wang 2 Mingxia Feng 2 Yuan Zhuang 4 Chen Hu 5 Yong He 6
Affiliations

Affiliations

  • 1 Department of Respiratory Medicine, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China. dpyyhxlili@tmmu.edu.cn.
  • 2 Department of Respiratory Medicine, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China.
  • 3 Department of Clinical Laboratory, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China.
  • 4 National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 5 Department of Respiratory Medicine, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China. huchen89@tmmu.edu.cn.
  • 6 Department of Respiratory Medicine, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, China. heyong@tmmu.edu.cn.
  • # Contributed equally.
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.

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