2. Academic Validation
  3. 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.
PMID: 35197546 DOI: 10.1038/s42003-022-03111-7
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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