Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are current standard of care for patients with EGFR mutation and metastatic non-small-cell lung carcinoma (NSCLC), but most patients using EGFR TKIs acquire resistance later. So, overcoming resistance of EGFR TKIs has become an important issue in the treatment of NSCLC. Previously, therapeutics targeting Bruton’s tyrosine kinase (BTK) have been successful in treating several hematologic malignancies. However, the role of BTK in NSCLC is still unknown. In this study, by examining surgical specimens from 80 NSCLC patients and their clinicopathologic parameters, we found significant correlation between high BTK expression and tumor differentiation, p-stage, lymph node metastatic status, maximum tumor size, and poor prognosis of patients. Using two NSCLC cell lines A540 and PC9, we demonstrated that BTKpos cells exhibited more stemness (OCT4, SOX2) and EMT (E-Cadherin, Slug) markers than BTKneg cells. Knockdown of BTK sensitized the NSCLC cells to Gefitinib. Meanwhile, the second-generation BTK inhibitor Acalabrutinib effectively suppressed SOX2, STAT3/JAK2/Akt axis and potentiated the anti-proliferative effect of Gefitinib and Osimertinib in NSCLC cells, including the T790M H1975 cells. Furthermore, Acalabrutinib and Osimertinib combination exhibited significant tumor growth inhibition of H1975-derived tumors in vivo. Our findings suggested that BTK mediates stemness and EMT properties, and inhibition of BTK potentiates the effect of Gefitinib and Osimertinib in NSCLC cells resistant to TKI. This implies a new approach to treat the NSCLC patients with resistance to previous TKI treatment.
Highlights
INTRODUCTON Lung cancer is the leading cause of cancer death worldwide, with an estimated global mortality of nearly 1.59 million in 2012 [1]
Bruton’s tyrosine kinase (BTK) expression correlates with clinicopathologic parameters and high expression of BTK is significantly associated with poor prognosis of Non-small-cell lung carcinoma (NSCLC) patients
The alveoli tissues were used as the control for adenocarcinoma, while bronchi tissues were used as the for 2 weeks to allow for tumor sphere formation
Summary
INTRODUCTON Lung cancer is the leading cause of cancer death worldwide, with an estimated global mortality of nearly 1.59 million in 2012 [1]. A key feature of BTK is its interaction with the PI3K/ Akt signaling pathway and function as the upstream of NF-kB and ERK, thereby affecting the proliferation, survival, and differentiation of lymphoma cells [12, 13]. These characteristics mean that BTK is ideal for drug development for the purpose of disrupting two major oncogenic pathways simultaneously. As for lung cancer, the BTK inhibitor ibrutinib effectively suppresses the proliferation of certain EGFR reciprocal receiver operating characteristic (ROC) curves regarding overall survival were generated.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
