Ping Xiao1, Lin-lin Sun2, Jing Wang2, Rui-li Han1, Qing Ma1, Dian-sheng Zhong1,2. 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.
Abstract
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 (RAD001). 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 RAD001 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, RAD001 combined with LY294002 markedly enhanced the growth inhibition on LKB1 wild-type H1792 cells and LKB1 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 (RAD001). 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 RAD001 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, RAD001 combined with LY294002 markedly enhanced the growth inhibition on LKB1 wild-type H1792 cells and LKB1 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.
Authors: Vanessa S Rodrik-Outmezguine; Sarat Chandarlapaty; Nen C Pagano; Poulikos I Poulikakos; Maurizio Scaltriti; Elizabeth Moskatel; José Baselga; Sylvie Guichard; Neal Rosen Journal: Cancer Discov Date: 2011-06-17 Impact factor: 39.397
Authors: Andrew X Zhu; Thomas A Abrams; Rebecca Miksad; Lawrence S Blaszkowsky; Jeffrey A Meyerhardt; Hui Zheng; Alona Muzikansky; Jeffrey W Clark; Eunice L Kwak; Deborah Schrag; Kathryn R Jors; Charles S Fuchs; A John Iafrate; Darrell R Borger; David P Ryan Journal: Cancer Date: 2011-04-27 Impact factor: 6.860
Authors: Brian M Wolpin; Aram F Hezel; Thomas Abrams; Lawrence S Blaszkowsky; Jeffrey A Meyerhardt; Jennifer A Chan; Peter C Enzinger; Brittany Allen; Jeffrey W Clark; David P Ryan; Charles S Fuchs Journal: J Clin Oncol Date: 2008-12-01 Impact factor: 44.544
Authors: Chuan Li; Wen-Yang Lin; Monte M Winslow; Hira Rizvi; Hongchen Cai; Christopher D McFarland; Zoe N Rogers; Maryam Yousefi; Ian P Winters; Charles M Rudin; Dmitri A Petrov Journal: Cancer Res Date: 2021-07-02 Impact factor: 12.701