The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of <scp>mTORC</scp>1/S6 signaling

Zhang, Bo; Wang, Linling; Zhang, Qi; Yan, Youyou; Jiang, Hong; Hu, Ruizhen; Zhou, Xinglu; Jiang, Feng; Lin, Nengming

doi:10.1002/1878-0261.12454

Cited by 9 publications

(16 citation statements)

References 29 publications

(34 reference statements)

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“…Recently, ibrutinib was expanded to treatment of some solid tumors, including pancreatic cancer, breast cancer, and NSCLC. However, it received no comforting effects as those of hematological malignancies (15,23,24). Our results suggested that the expression of BTK was decreased in the advancing stages of LUAD patients, which seemed to be inconsistent with hematological malignancies.…”

Section: Discussionmentioning

confidence: 60%

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining

Wei

Qin

et al. 2020

Front. Oncol.

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Tumor microenvironment (TME) plays a crucial role in the initiation and progression of lung adenocarcinoma (LUAD); however, there is still a challenge in understanding the dynamic modulation of the immune and stromal components in TME. In the presented study, we applied CIBERSORT and ESTIMATE computational methods to calculate the proportion of tumor-infiltrating immune cell (TIC) and the amount of immune and stromal components in 551 LUAD cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were analyzed by COX regression analysis and protein-protein interaction (PPI) network construction. Then, Bruton tyrosine kinase (BTK) was determined as a predictive factor by the intersection analysis of univariate COX and PPI. Further analysis revealed that BTK expression was negatively correlated with the clinical pathologic characteristics (clinical stage, distant metastasis) and positively correlated with the survival of LUAD patients. Gene Set Enrichment Analysis (GSEA) showed that the genes in the high-expression BTK group were mainly enriched in immune-related activities. In the low-expression BTK group, the genes were enriched in metabolic pathways. CIBERSORT analysis for the proportion of TICs revealed that B-cell memory and CD8+ T cells were positively correlated with BTK expression, suggesting that BTK might be responsible for the preservation of immune-dominant status for TME. Thus, the levels of BTK might be useful for outlining the prognosis of LUAD patients and especially be a clue that the status of TME transition from immune-dominant to metabolic activity, which offered an extra insight for therapeutics of LUAD.

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Section: Discussionmentioning

confidence: 60%

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining

Wei

Qin

et al. 2020

Front. Oncol.

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“…Based on these, a series of derivatives are obtained. Ibr-7 is a promising candidate and exhibites great anti-tumor toward NSCLC and pancreatic cancer [15,16]. Meanwhile, ibrutinib (10 µmol/L) has been shown radiosensitivity of pancreatic cancer cell lines in our previous study [17].…”

Section: Discussionmentioning

confidence: 99%

“…Ibr-7 is a newly synthesized derivative of ibrutinib that showed anti-tumor activity against various cancer cells compared with its the parental compound [15]. To determine the anti-proliferation effect of Ibr-7 in pancreatic cancer cells, both two pancreatic cancer cells were treated with increasing doses of ibrutinib or Ibr-7 (1.56-25 µmol/L) for 24 h, 48 h or 72 h respectively and changes in cell proliferation were examined by CCK-8 assay.…”

Section: Ibr-7 Induced Cell Growth Inhibition In Pancreatic Cancer Cellsmentioning

confidence: 99%

“…It exhibited potent antitumor effect against various cancers, including lymphoma and solid tumors (such as non-small cell lung cancer and pancreatic cancer) [10][11][12][13][14]. However, in our previous research, it was demonstrated that ibrutinib's anti-tumor effect was limited to blood cancer cells [15]. The clinical trials of ibrutinib in solid tumors are facing dilemma.…”

Section: Introductionmentioning

confidence: 99%

“…The clinical trials of ibrutinib in solid tumors are facing dilemma. Based on these, we synthesized a series of ibrutinib derivatives, of which Ibr-7 exhibited great anti-tumor toward NSCLC and pancreatic cancer [15,16]. Besides, in our previous research ibrutinib (10 µmol/L) has been shown to enhance the effects of radiation therapy [17].…”

Section: Introductionmentioning

confidence: 99%

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The Ibr-7 Derivative of Ibrutinib Exhibits Radiosensitivity in Pancreatic Cancer Cells via Targeting EGFR

Tan¹,

Zhang²,

Yan

et al. 2020

Preprint

Self Cite

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Background: Radiotherapy is one of the main therapeutic methods for pancreatic cancer, but radiation resistance limits the clinical application. As a result, novel therapeutic agents to improve the radiosensitivity is urgent. This study aimed to investigate the effect of Ibr-7 (the derivative of ibrutinib) on radiosensitivity of human pancreatic cancer cells.Methods: The effect of Ibr-7 on pancreatic cancer cell’s proliferation were detected by CCK-8 assay. Radiosensitivity was assessed by clonogenic formation assay. Cell cycle, cell apoptosis were analyzed by flow cytometry. DNA damage was detected by immunofluorescence analysis. The expression of p-EGFR, EGFR were determined by western blot.Results: Ibr-7 showed anti-proliferative effect in PANC-1 and Capan2 cells in a dose- and time-dependent manner. Ibr-7 (2 µmol/L) enhanced the effect of radiation in PANC-1 and Capan2 cells. Further findings showed that this combination enhanced G2/M phase arrest and increased cell apoptosis. Additional molecular mechanism studies revealed that the expression of p-EGFR was decreased by Ibr-7 alone or combined with radiation. Overexpression of EGFR reversed the cell apoptosis induced by Ibr-7 combined with radiation. Moreover, the expression of γ-H2AX was significantly decreased in Ibr-7 combined with radiation group.Conclusions: Our study indicated that the potential application of Ibr-7 as a highly effective radiosensitizer for the treatment of pancreatic cancer cells.

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Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness

Liu

Huang

et al. 2021

Oncogenesis

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Locally advanced oral squamous cell carcinoma (OSCC) requires multimodal therapy, including surgery and concurrent chemoradiotherapy (CCRT). CCRT-resistant and recurrent cancer has a poor prognosis. We investigated the effects of Bruton’s tyrosine kinase (BTK) on CCRT-resistant OSCC tissues. The effect of ibrutinib, a first-in-class BTK inhibitor, was tested on stem cell-like OSCC tumorspheres. A tissue array was constructed using tissue samples from 70 patients with OSCC. Human OSCC cell lines, SAS, TW2.6 and HSC-3, were examined. Wound healing, Matrigel invasion, and tumorsphere formation assays, as well as immunofluorescence analysis and flow cytometry, were used to investigate the effects of BTK knockdown (shBTK), ibrutinib, cisplatin, and ibrutinib/cisplatin combination on OSCC cells. We demonstrated that BTK was aberrantly highly expressed in the clinical CCRT-resistant OSCC tissue array, which resulted in poor overall survival in our local Tri-Service General Hospital and freely accessible TCGA OSCC cohorts. shBTK significantly downregulated the stemness markers Nanog, CD133, T cell immunoglobulin-3 (TIM-3), and Krüppel-like factor 4 (KLF4) in SAS tumorspheres and attenuated OSCC cell migration and colony formation. Ibrutinib reduced the number of aldehyde dehydrogenase (ALDH)-rich OSCC cells and reduced tumorsphere formation, migration, and invasion in a dose-dependent manner. Compared with ibrutinib or cisplatin monotherapy, the ibrutinib/cisplatin combination significantly reduced the formation of ALDH + OSCC tumorspheres and enhanced apoptosis. These results demonstrate that ibrutinib effectively inhibits the CSCs-like phenotype of OSCC cells through dysregulation of BTK/CD133 signaling. The ibrutinib/cisplatin combination may be considered for future clinical use.

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The Ibr‐7 derivative of ibrutinib exhibits enhanced cytotoxicity against non‐small cell lung cancer cells via targeting of mTORC1/S6 signaling

Cited by 9 publications

References 29 publications

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining

The Ibr-7 Derivative of Ibrutinib Exhibits Radiosensitivity in Pancreatic Cancer Cells via Targeting EGFR

Inhibition of Bruton’s tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness

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