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.

Focal adhesion kinase confers lenvatinib resistance in hepatocellular carcinoma via the regulation of lysine‐deficient kinase 1

“…48,49 Our previous data demonstrated that FAK plays a crucial role in hepatocarcinogenesis in mouse models. [16][17][18] Furthermore, FAK has been reported to be a key player in chemo-and targeted drug-resistance in various solid tumors, such as lung, 19,20 head and neck, 21 and breast 22 cancers, where FAK inhibition provoked effective growth inhibition and apoptosis in acquired resistant cells and xenografts. For example, acquired resistant HCC exhibited upregulated and persistent FAK phosphorylation, which mediated doxorubicin (DOX) resistance in HCC patient samples and cell lines; however, FAK signaling suppression sensitized DOX-resistant HCC cells to DOX treatment.…”

“…Focal adhesion kinase (FAK), as a cytoplasmic nonreceptor tyrosin protein kinase (PTK2), has been demonstrated playing a crucial role in HCC development in our previous findings together with others. [15][16][17][18] Furthermore, FAK has been reported to be a key player in chemo-and targeted drugresistance in various solid tumors, such as lung, 19,20 head and neck, 21 and breast 22 cancers. However, the role of FAK in drug resistance in liver cancer remains largely unclear.…”

Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies

“…By upregulation of laminin α5, IL-6 remodeled ECM and activated a downstream target focal adhesion kinase (FAK), thus contributing to acquired resistance against Osimertinib. [183][184][185] FAK activation was confirmed to be dispensable for IL-6 production in the maintenance of mesenchymal stem cells and can lead to acquired resistance of gefitinib as well. 186,187 CONTRIBUTION OF TCP TO TARGETED THERAPY RESISTANCE Targeted therapy is one of the most successful treatments that strike at the heart of a wide range of cancers.…”

“…178,179 Cytokines secreted by immune and stromal cells also provide clues for acquired TCP induced by targeted therapy. [180][181][182] According to Li et al, 183 IL-6 in EFGR-mutant NSCLC patients was significantly increased upon osimertinib therapy. This associated Upregulation of laminin α5, which is among the most widely distributed laminins and is a major component of extracellular matrix (ECM), also occurred.…”

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

“…It was revealed that interleukin 6 (IL-6) leads to osimertinib resistance by binding to its receptors and activating LAMA5/FAK signaling. 165 Tumor necrosis factor (TNF) is a mediator of intrinsic resistance to EGFR-TKIs. TNF binds to TNFR and activates the c-Jun N-terminal kinase (JNK) to increase growth arrest-specific 6 (Gas6) expression, which binds to AXL, activates ERK signaling, and resists EGFR inhibition.…”