LKB1 gene inactivation does not sensitize non-sma cell lung cancer cells to mTOR inhibitors in vitro  

作　　者：Ping XIAO Lin-lin SUN Jing WANG Rui-li HAN Qing MA Dian-sheng ZHONG 

机构地区：[1]Department of Oncology, Tianjin Medical University General Hospital, Tianjin 300052, China [2]Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China

出　　处：《Acta Pharmacologica Sinica》2015年第9期1107-1112,共6页中国药理学报（英文版）

基　　金：This study was supported by grants from the National Natural Science Foundation of China （81071915 and 31301160） and the Tianjin Health Bureau （2011KZ107）.

摘　　要：Aim： Previous study has shown that endometrial cancers with LKB1 inactivation are highly responsive to mTOR inhibitors. In this study we examined the effect of LKB1 gene status on mTOR inhibitor responses in non-small cell lung cancer （NSCLC） cells. Methods： Lung cancer cell lines Calu-1, H460, H1299, H1792, and A549 were treated with the mTOR inhibitors rapamycin or everolimus （RADO01）. The mTOR activity was evaluated by measuring the phosphorylation of 4EBP1 and S6K, the two primary mTOR substrates. Cells proliferation was measured by MTS or sulforhodamine B assays. Results： The basal level of mTOR activity in LKB1 mutant A549 and H460 cells was significantly higher than that in LKB1 wild-type Calu-1 and H1792 cells. However, the LKB1 mutant A549 and H460 cells were not more sensitive to the mTOR inhibitors than the LKB1 wild-type Calu-1 and H1792 cells. Moreover, knockdown of LKB1 gene in H1299 cells did not increase the sensitivity to the mTOR inhibitors. Treatment with rapamycin or RADO01 significantly increased the phosphorylation of AKT in both LKB1 wild-type and LKB1 mutant NSCLC cells, which was attenuated by the PI3K inhibitor LY294002. Furthermore, RADO01 combined with LY294002 markedly enhanced the growth inhibition on LKB1 wild-type H1792 cells and LKI31 mutant A549 cells. Conclusion： LKB1 gene inactivation in NSCLC cells does not increase the sensitivity to the mTOR inhibitors. The negative feedback activation of AKT by mTOR inhibition may contribute to the resistance of NSCLC cells to mTOR inhibitors.Aim： Previous study has shown that endometrial cancers with LKB1 inactivation are highly responsive to mTOR inhibitors. In this study we examined the effect of LKB1 gene status on mTOR inhibitor responses in non-small cell lung cancer （NSCLC） cells. Methods： Lung cancer cell lines Calu-1, H460, H1299, H1792, and A549 were treated with the mTOR inhibitors rapamycin or everolimus （RADO01）. The mTOR activity was evaluated by measuring the phosphorylation of 4EBP1 and S6K, the two primary mTOR substrates. Cells proliferation was measured by MTS or sulforhodamine B assays. Results： The basal level of mTOR activity in LKB1 mutant A549 and H460 cells was significantly higher than that in LKB1 wild-type Calu-1 and H1792 cells. However, the LKB1 mutant A549 and H460 cells were not more sensitive to the mTOR inhibitors than the LKB1 wild-type Calu-1 and H1792 cells. Moreover, knockdown of LKB1 gene in H1299 cells did not increase the sensitivity to the mTOR inhibitors. Treatment with rapamycin or RADO01 significantly increased the phosphorylation of AKT in both LKB1 wild-type and LKB1 mutant NSCLC cells, which was attenuated by the PI3K inhibitor LY294002. Furthermore, RADO01 combined with LY294002 markedly enhanced the growth inhibition on LKB1 wild-type H1792 cells and LKI31 mutant A549 cells. Conclusion： LKB1 gene inactivation in NSCLC cells does not increase the sensitivity to the mTOR inhibitors. The negative feedback activation of AKT by mTOR inhibition may contribute to the resistance of NSCLC cells to mTOR inhibitors.

关 键 词：non small-cell lung cancer mTOR protein liver kinase B1 AKT RAPAMYCIN RAD001 LY294002 

分 类 号：Q782[生物学—分子生物学] Q71