AI Article Synopsis
- Small cell lung cancer (SCLC) is aggressive and lacks effective targeted therapies, but research reveals that 92% of SCLC cell lines have issues with the PI3K/AKT/mTOR pathway.
- The study found that the phosphorylation of 4E-BP1 is linked to how sensitive SCLC cells are to treatments like RAD001 and BEZ235, which target mTOR and PI3K/mTOR respectively.
- Combining RAD001 and BEZ235 not only inhibits SCLC cell growth better than either drug alone but also enhances cell cycle arrest and apoptosis, suggesting this combination could be a promising treatment approach and that p-4E-BP1 might predict treatment response.
Article 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, 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739750 | PMC |
| http://dx.doi.org/10.18632/oncotarget.18984 | DOI Listing |
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