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

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 a...

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Veröffentlicht in:Oncogenesis (New York, NY) NY), 2021-07, Vol.10 (7), p.56-56, Article 56
Hauptverfasser: Yeh, Chi-Tai, Chen, Tzu-Tao, Satriyo, Pamungkas Bagus, Wang, Chun-Hua, Wu, Alexander T. H., Chao, Tsu-Yi, Lee, Kang-Yun, Hsiao, Michael, Wang, Liang-Shun, Kuo, Kuang-Tai
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container_issue 7
container_start_page 56
container_title Oncogenesis (New York, NY)
container_volume 10
creator Yeh, Chi-Tai
Chen, Tzu-Tao
Satriyo, Pamungkas Bagus
Wang, Chun-Hua
Wu, Alexander T. H.
Chao, Tsu-Yi
Lee, Kang-Yun
Hsiao, Michael
Wang, Liang-Shun
Kuo, Kuang-Tai
description 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.
doi_str_mv 10.1038/s41389-021-00345-8
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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. 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subjects 13
13/100
13/109
13/2
13/31
13/51
13/89
631/154/53/2422
631/67/1612/1350
AKT protein
Apoptosis
Bruton's tyrosine kinase
Cell Biology
E-cadherin
Epidermal growth factor
Epidermal growth factor receptors
Gefitinib
Human Genetics
Internal Medicine
Janus kinase 2
Life Sciences & Biomedicine
Lung cancer
Lung carcinoma
Lymph nodes
Medicine
Medicine & Public Health
Metastases
Metastasis
Non-small cell lung carcinoma
Oct-4 protein
Oncology
Patients
Protein-tyrosine kinase
Science & Technology
Stat3 protein
Targeted cancer therapy
Tumors
title Bruton’s tyrosine kinase (BTK) mediates resistance to EGFR inhibition in non-small-cell lung carcinoma
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