Abstract
BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR.
Highlights
B-cell lymphoma protein 2 (Bcl-2) interacting mediator of cell death (BIM) is a proapoptotic protein that initiates apoptosis triggered by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). mammalian target of rapamycin (mTOR) negatively regulates apoptosis and may influence response to EGFR TKI
It is recognized that TKIs eliminate tumour cells by inducing a form of cell death called apoptosis, which is governed by the B-cell lymphoma protein 2 (Bcl-2) family of proteins and mitochondria[5]
The mTOR kinase serves as the catalytic subunit of two multiprotein complexes with distinct functions: mTOR complex 1, a rapamycin and nutrient-sensitive complex, defined by the regulatory associated protein of mTOR (Raptor), and mTOR complex 2, a growth-factor-sensitive but nutrient-insensitive complex, defined by the rapamycin-insensitive companion of mTOR (Rictor) (Fig. 1)[10]
Summary
BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We identified high levels of BIM mRNA expression as a predictive marker of response, progression-free survival (PFS) and overall survival (OS) in erlotinib-treated EGFR-mutant NSCLC patients[8]. In resistant melanoma cell lines, vemurafenib (BRAF inhibitor) or selumetinib (MEK inhibitor) either fail to suppress P-ERK or resistance emerges through the activity of mammalian target of rapamycin (mTOR), despite P-ERK suppression and BIM induction[9]. This suggests that BIM regulation is MAPK-dependent, but mTOR-independent, and BIM up-regulation is not always sufficient to promote apoptosis[9]. The mTOR kinase serves as the catalytic subunit of two multiprotein complexes with distinct functions: mTOR complex 1 (mTORC1), a rapamycin and nutrient-sensitive complex, defined by the regulatory associated protein of mTOR (Raptor), and mTOR complex 2 (mTORC2), a growth-factor-sensitive but nutrient-insensitive complex, defined by the rapamycin-insensitive companion of mTOR (Rictor) (Fig. 1)[10]
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