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.
Highlights
Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-tyrosine kinase inhibitors (TKIs)), is the first-line standard-of-care for Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients, while acquired drug resistance will inevitably occur
We found that IL-6 mediated osimertinib resistance through Laminin α5/ focal adhesion kinase (FAK) signaling activation, which can be overcome by ibrutinib, identified by compound screening (Fig. 6f)
Our findings suggest that ibrutinib in combination with osimertinib may be developed as a promising strategy to overcome IL-6 induced osimertinib resistance
Summary
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) has been indicated as a potential resistance mechanism to EGFR-TKIs. IL-6 represents a keystone cytokine in infection, cancer, and inflammation, which can be produced by multiple cell types in the tumor microenvironment, leading to JAK/STAT3 signaling activation in both tumor cells and tumor‐infiltrating immune cells, and promoted the proliferation, survival, invasiveness, and metastasis of tumor cells, while strongly suppressing the anti-tumor immune response[7,8]. In EGFR-mutant NSCLC treated with first-line 1st generation EGFR-TKIs, a high baseline level of serum IL-6 was associated with shorter progression-free survival (PFS)[11,12] It is unknown whether IL-6 may influence osimertinib efficacy or be associated with osimertinib resistance. The current study aimed to identify whether IL-6 was correlated with osimertinib efficacy and found that Laminin α5/ FAK signaling activation mediates IL-6-induced osimertinib resistance, which could be overcame by ibrutinib in combination with osimertinib
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