Abstract
BackgroundLung 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.MethodsThe 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.ResultsBEZ235 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.ConclusionsThe 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.
Highlights
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)
BEZ235 exerts potent in vitro antigrowth effects against non-small-cell lung cancer (NSCLC) cell lines with different EGFR status Based on the premise of aberrant EGFR and phosphoinositide 3-kinase (PI3K)/ mechanistic target of rapamycin (mTOR) signaling in lung cancer [4, 6], we investigated the antiproliferative activity of the dual PI3K/mTOR inhibitor BEZ235 in 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
BEZ235 effectively suppressed the growth of PC9-IR, H1975 and CL97 cell lines, with acquired EGFR-TKI resistance
Summary
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). Small-molecule epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) that compete with ATP binding and inhibit downstream signal transduction have been developed as part of these efforts. These EGFR-TKIs, such as gefitinib and erlotinib, have proven to be effective in non-small cell lung cancer (NSCLC) patients carrying specific activating mutations in the tyrosine kinase domain of EGFR, mostly within exon 18–21, such as the L858R point mutation and deletions in exon 19 [4,5,6]. Recent studies have revealed several molecular mechanisms underlying EGFR-TKI resistance, including a second mutation at T790 M in exon 20 of EGFR, activation of alternative receptor tyrosine kinases (RTKs) or PI3K signaling, small-cell lung cancer (SCLC) transformation, and epithelial-mesenchymal transition (EMT) [8,9,10]
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