Bruton’s tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma

Chi Tai Yeh, Tzu Tao Chen, Pamungkas Bagus Satriyo, Chun Hua Wang, Alexander T.H. Wu, Tsu Yi Chao, Kang Yun Lee, Michael Hsiao, Liang Shun Wang, Kuang Tai Kuo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number56
JournalOncogenesis
Volume10
Issue number7
DOIs
Publication statusPublished - Jul 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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