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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | NSCLC | Research

The dual PI3K/mTOR inhibitor BEZ235 restricts the growth of lung cancer tumors regardless of EGFR status, as a potent accompanist in combined therapeutic regimens

Authors: Yi-Ying Wu, Hung-Chang Wu, Jia-En Wu, Kuo-Yen Huang, Shuenn-Chen Yang, Si-Xuan Chen, Chao-Jung Tsao, Keng-Fu Hsu, Yuh-Ling Chen, Tse-Ming Hong

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

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Abstract

Background

Lung cancer is the most common cause of cancer-related mortality worldwide despite diagnostic improvements and the development of targeted therapies, notably including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling has been shown to contribute to tumorigenesis, tumor progression, and resistance to therapy in most human cancer types, including lung cancer. Here, we explored the therapeutic effects of co-inhibition of PI3K and mTOR in non-small-cell lung cancer (NSCLC) cells with different EGFR status.

Methods

The antiproliferative activity of a dual PI3K/mTOR inhibitor BEZ235 was examined by the WST-1 assay and the soft agar colony-formation assay in 2 normal cell lines and 12 NSCLC cell lines: 6 expressing wild-type EGFR and 6 expressing EGFR with activating mutations, including exon 19 deletions, and L858R and T790 M point mutations. The combination indexes of BEZ235 with cisplatin or an EGFR-TKI, BIBW2992 (afatinib), were calculated. The mechanisms triggered by BEZ235 were explored by western blotting analysis. The anti-tumor effect of BEZ235 alone or combined with cisplatin or BIBW2992 were also studied in vivo.

Results

BEZ235 suppressed tumor growth in vitro and in vivo by inducing cell-cycle arrest at G1 phase, but without causing cell death. It also reduced the expression of cyclin D1/D3 by regulating both its transcription and protein stability. Moreover, BEZ235 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells by enhancing or prolonging DNA damage and BIBW2992-induced apoptosis in EGFR-TKI–resistant NSCLC cells containing a second TKI-resistant EGFR mutant.

Conclusions

The dual PI3K/mTOR inhibition by BEZ235 is an effective antitumor strategy for enhancing the efficacy of chemotherapy or targeted therapy, even as a monotherapy, to restrict tumor growth in lung cancer treatment.
Appendix
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Metadata
Title
The dual PI3K/mTOR inhibitor BEZ235 restricts the growth of lung cancer tumors regardless of EGFR status, as a potent accompanist in combined therapeutic regimens
Authors
Yi-Ying Wu
Hung-Chang Wu
Jia-En Wu
Kuo-Yen Huang
Shuenn-Chen Yang
Si-Xuan Chen
Chao-Jung Tsao
Keng-Fu Hsu
Yuh-Ling Chen
Tse-Ming Hong
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1282-0

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