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

Xiao P, Sun LL, Wang J, Han RL, Ma Q, Zhong DS - Acta Pharmacol. Sin. (2015)

Bottom Line: 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.Moreover, knockdown of LKB1 gene in H1299 cells did not increase the sensitivity to the mTOR inhibitors.Furthermore, RAD001 combined with LY294002 markedly enhanced the growth inhibition on LKB1 wild-type H1792 cells and LKB1 mutant A549 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, 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.

No MeSH data available.


Related in: MedlinePlus

Combined PI3K and mTOR inhibitors synergistically inhibited cell growth. Cell growth inhibition was tested by treatment with LY294002 (10 μmol/L) or RAD001 (10 nmol/L) as single agents or with combined LY294002 (10 μmol/L) and RAD001 (10 nmol/L) for 72 h. Statistical significance was evaluated using one-way analysis of variance. bP<0.05.
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fig4: Combined PI3K and mTOR inhibitors synergistically inhibited cell growth. Cell growth inhibition was tested by treatment with LY294002 (10 μmol/L) or RAD001 (10 nmol/L) as single agents or with combined LY294002 (10 μmol/L) and RAD001 (10 nmol/L) for 72 h. Statistical significance was evaluated using one-way analysis of variance. bP<0.05.

Mentions: Because PI3K is required for RAD001-induced activation of AKT, we speculated that PI3K inhibition by LY294002 combined with RAD001 might increase growth inhibition. To investigate this possibility, H1792 and A549 cells were treated with RAD001 alone or in combination with LY294002 for 72 h, and MTS assays were performed. As expected, the combination of RAD001 and LY294002 enhanced the antitumor effects (Figure 4A, 4B).


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

Xiao P, Sun LL, Wang J, Han RL, Ma Q, Zhong DS - Acta Pharmacol. Sin. (2015)

Combined PI3K and mTOR inhibitors synergistically inhibited cell growth. Cell growth inhibition was tested by treatment with LY294002 (10 μmol/L) or RAD001 (10 nmol/L) as single agents or with combined LY294002 (10 μmol/L) and RAD001 (10 nmol/L) for 72 h. Statistical significance was evaluated using one-way analysis of variance. bP<0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4561965&req=5

fig4: Combined PI3K and mTOR inhibitors synergistically inhibited cell growth. Cell growth inhibition was tested by treatment with LY294002 (10 μmol/L) or RAD001 (10 nmol/L) as single agents or with combined LY294002 (10 μmol/L) and RAD001 (10 nmol/L) for 72 h. Statistical significance was evaluated using one-way analysis of variance. bP<0.05.
Mentions: Because PI3K is required for RAD001-induced activation of AKT, we speculated that PI3K inhibition by LY294002 combined with RAD001 might increase growth inhibition. To investigate this possibility, H1792 and A549 cells were treated with RAD001 alone or in combination with LY294002 for 72 h, and MTS assays were performed. As expected, the combination of RAD001 and LY294002 enhanced the antitumor effects (Figure 4A, 4B).

Bottom Line: 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.Moreover, knockdown of LKB1 gene in H1299 cells did not increase the sensitivity to the mTOR inhibitors.Furthermore, RAD001 combined with LY294002 markedly enhanced the growth inhibition on LKB1 wild-type H1792 cells and LKB1 mutant A549 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, 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.

No MeSH data available.


Related in: MedlinePlus