Combination treatment of RAD001 and BEZ235 exhibits synergistic antitumor activity via down-regulation of p-4E-BP1/Mcl-1 in small cell lung cancer.

Bo Hong,Ke Deng,Wei Wang,Huogang Wang,Vivian Wai Yan Lui,Wenchu Lin,Haiming Dai

doi:10.18632/oncotarget.18984

Abstract

Small cell lung cancer (SCLC) is a highly malignant cancer with few targeted therapies. In the study, by mining the Cancer Cell Line Encyclopedia (CCLE) database, we found that PI3K/AKT/mTOR pathway was aberrant in 92% of SCLC cell lines. Moreover, we found that the phosphorylation level of 4E-BP1 was significantly correlated with SCLC sensitivity to RAD001 (mTOR inhibitor) and BEZ235 (PI3K/mTOR dual inhibitor). Combination of RAD001 and BEZ235 synergistically inhibited the growth of SCLC cells, which was accompanied by enhanced induction of cell cycle arrest and apoptosis. Such a combination dramatically inhibited the activation of AKT, and strongly reduced the phosphorylation of 4E-BP1 and its downstream target Mcl-1. Knock-down of Mcl-1 enhanced the growth inhibition of SCLC cells induced by RAD001 and BEZ235 co-treatment, whereas over-expression of Mcl-1 reduced the growth inhibitory effect. Furthermore, in vivo study demonstrated that the combination treatment suppressed tumor growth more effectively than RAD001 or BEZ235 treatment alone. In summary, our study suggests that combination of BEZ235 and RAD001 may be an effective regimen for SCLC treatment, and p-4E-BP1 may serve as a predictive biomarker for SCLC response to mTOR inhibitor.

Highlights

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer accounting for 10~15% of the total lung cancer cases
By mining the Cancer Cell Line Encyclopedia (CCLE) database, we found that PI3K/AKT/mTOR pathway was aberrant in 92% of SCLC cell lines
Recurrent mutations reported by COSMIC and oncogenic mutations confirmed by previous study were marked in the MutationMapper (Supplementary Figure 1). These results indicate that PI3K/AKT/mTOR signaling is aberrant in SCLC cell lines

Summary

Introduction

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer accounting for 10~15% of the total lung cancer cases. SCLC differs from nonsmall cell lung cancer (NSCLC) in having neuroendocrine differentiation, higher proliferation index and a tendency to metastasize earlier [1]. At the time of diagnosis, over 70% of SCLC patients are presented with extensive stage disease (SCLC has spread beyond the supraclavicular areas, or with distant metastasis) [2]. Chemotherapy with cisplatin and etoposide is the standard treatment for extensive stage SCLC, and the initial response rate is high. Extensive stage SCLC has an extremely very poor prognosis with overall 5-year survival rate of 1%–2%. Effective new therapy for advanced SCLC patients is needed [3, 4]

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Results

Conclusion