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

doi:10.1038/s41389-021-00345-8

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

Oncogenesis. 2021 Jul 27;10(7):56. doi: 10.1038/s41389-021-00345-8.

Authors

Chi-Tai Yeh^#^{1

2

3}, Tzu-Tao Chen^#^{4

5}, Pamungkas Bagus Satriyo^{1

6

7}, Chun-Hua Wang^{8

9}, Alexander T H Wu¹⁰, Tsu-Yi Chao^{2

11}, Kang-Yun Lee^{4

5

11}, Michael Hsiao¹², Liang-Shun Wang¹³, Kuang-Tai Kuo^{14

15}

Affiliations

¹ Department of Medical Research and Education, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
² Division of Hematology & Oncology, Department of Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
³ Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu City, Taiwan.
⁴ Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
⁵ Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁶ Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
⁷ Faculty of Medicine Public Health and Nursing, Department of Pharmacology and Therapy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
⁸ Department of Dermatology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan.
⁹ School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan.
¹⁰ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
¹¹ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
¹² Genomics Research Center, Academia Sinica, Taipei, Taiwan.
¹³ Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
¹⁴ Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan. ktkuo@tmu.edu.tw.
¹⁵ Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. ktkuo@tmu.edu.tw.

^# Contributed equally.

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 BTK^pos cells exhibited more stemness (OCT4, SOX2) and EMT (E-Cadherin, Slug) markers than BTK^neg 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.