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Br J Cancer
2010 Aug 24;1035:622-8. doi: 10.1038/sj.bjc.6605761.
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Dual inhibition of EGFR and mTOR pathways in small cell lung cancer.
Schmid K
,
Bago-Horvath Z
,
Berger W
,
Haitel A
,
Cejka D
,
Werzowa J
,
Filipits M
,
Herberger B
,
Hayden H
,
Sieghart W
.
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BACKGROUND: In this report we investigated the combination of epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) pathway inhibition as a possible new therapeutic strategy for small cell lung cancer (SCLC).
METHODS: EGFR, p-AKT, p-ERK, p-mTOR and p-p70s6K protein expressions were studied by immunohistochemistry in 107 small cell lung carcinomas and correlated with clinicopathological parameters. Cells of SCLC were treated with erlotinib+/-RAD001 and analysed for cell viability, proliferation, autophagy, and pathway regulation.
RESULTS: Epidermal growth factor receptor, p-AKT, p-ERK, p-mTOR, and p-p70s6K were expressed in 37, 24, 13, 55 and 91% of the tumour specimens of all SCLC patients, respectively, and were not associated with disease-free or overall survival. The expression of EGFR was lower in neoadjuvant-treated patients (P=0.038); mTOR pathway activation was higher in the early stages of disease (P=0.048). Coexpression of EGFR/p-mTOR/p-p70s6K was observed in 28% of all patients . EGFR immunoreactivity was associated with p-ERK and p-mTOR expression (P=0.02 and P=0.0001); p-mTOR immunoreactivity was associated with p-p70s6K expression (P=0.001). Tumour cells comprised a functional EGFR, no activating mutations in exons 18-21, and resistance to RAD001 monotherapy. We found synergistic effects of erlotinib and RAD001 combination therapy on the molecular level, cell viability, proliferation and autophagy.
CONCLUSIONS: The combined inhibition of EGFR/mTOR pathways could be a promising approach to treat SCLC.
Figure 1. Immunostaining of EGFR and mTOR pathways in SCLC. Immunohistochemical staining of SCLC for (A) p-mTOR, (B) p-p70s6K (strongly stained mitoses are marked by arrows), (C) p-AKT, (D) p-ERK and (E) EGFR (all magnification × 400).
Figure 2. Effects on cell growth after treatment of SCLC cells with erlotinib, RAD001 and a combination of both. GLC-4 (A) and VL-68 (B) cells were treated with increasing doses of RAD001, erlotinib or a combination of both for 72 h and analysed for cell viability using the MTT assay. Data are given as mean percentage of viable cells±s.d. *Statistical significance (P<0.05). (C) VL-68 cells were treated with erlotinib 5 μ or increasing doses of RAD001 as indicated or a combination of both for 24 h, and thereafter were analysed using the 3H-thymidine assay. Data are given as mean counts per min±s.d. *Statistical significance (P<0.05). (D) GLC-4 cells were treated with 5 μ erlotinib, 10 n RAD001 or a combination of both for 24 h and analysed by FACS after propidium iodide staining. Data are given as mean percentage of cells±s.d. *Statistical significance (P<0.05). (E) VL-68 and GLC-4 cells were treated with 5 μ erlotinib and 100 n RAD001 or a combination of both for 48 h and analysed for acidic vesicular organelles. Data are given as x-fold autophagy-positive cells – one of three representative experiments is shown.
Figure 3. Effects on EGFR and mTOR pathways after treatment of SCLC cells with erlotinib, RAD001 and a combination of both. (A) GLC-4 and VL-68 cells do express EGFR. (B) GCL-4 and VL-68 cells were treated with 5 μ erlotinib±EGF (100 ng ml–1) for 10 min and blotted for p-ERK, p-AKT and respective total proteins. (C) VL-68 and GCL-4 cells were treated with 5 μ erlotinib, 5 n RAD001 or a combination of both for 24 h, and then immunoblotted for total and phospho-protein expression of AKT, ERK, mTOR and p70s6K.
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