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Potentiation of Growth Inhibitory Responses of the mTOR Inhibitor Everolimus by Dual mTORC1/2 Inhibitors in Cultured Breast Cancer Cell Lines.

Leung EY, Askarian-Amiri M, Finlay GJ, Rewcastle GW, Baguley BC - PLoS ONE (2015)

Bottom Line: We then carried out combination studies with four everolimus resistant triple-negative breast cancer cell lines, and found an unexpectedly high degree of synergy between everolimus and the other inhibitors tested.The level of potentiation of everolimus inhibitory activity (measured by IC50 values) was found to be cell line-specific for all the kinase inhibitors tested.The results suggest that judicious combination of mTOR inhibitors with different modes of action could have beneficial effects in the treatment of breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Auckland Cancer Society Research Centre, University of Auckland, Grafton, Auckland, New Zealand; Department of Molecular Medicine and Pathology, University of Auckland, Grafton, Auckland, New Zealand.

ABSTRACT
The mammalian target of rapamycin (mTOR), a vital component of signaling pathways involving PI3K/AKT, is an attractive therapeutic target in breast cancer. Everolimus, an allosteric mTOR inhibitor that inhibits the mTOR functional complex mTORC1, is approved for treatment of estrogen receptor positive (ER+) breast cancer. Other mTOR inhibitors show interesting differences in target specificities: BEZ235 and GSK2126458 are ATP competitive mTOR inhibitors targeting both PI3K and mTORC1/2; AZD8055, AZD2014 and KU-0063794 are ATP competitive mTOR inhibitors targeting both mTORC1 and mTORC2; and GDC-0941 is a pan-PI3K inhibitor. We have addressed the question of whether mTOR inhibitors may be more effective in combination than singly in inhibiting the proliferation of breast cancer cells. We selected a panel of 30 human breast cancer cell lines that included ER and PR positive, HER2 over-expressing, and "triple negative" variants, and determined whether signaling pathway utilization was related to drug-induced inhibition of proliferation. A significant correlation (p = 0.005) was found between everolimus IC50 values and p70S6K phosphorylation, but not with AKT or ERK phosphorylation, consistent with the mTOR pathway being a principal target. We then carried out combination studies with four everolimus resistant triple-negative breast cancer cell lines, and found an unexpectedly high degree of synergy between everolimus and the other inhibitors tested. The level of potentiation of everolimus inhibitory activity (measured by IC50 values) was found to be cell line-specific for all the kinase inhibitors tested. The results suggest that judicious combination of mTOR inhibitors with different modes of action could have beneficial effects in the treatment of breast cancer.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of a network of PI3K/AKT/mTOR signaling.Inhibitors targeting the pathways are used in this study. Blue arrows and black lines represent activating and inhibitory connections, respectively. GDC-0941, pan-PI3K inhibitor; BEZ235 and GSK2126458, dual PI3K/mTOR kinase inhibitors; AZD8055, AZD82014 and KU-0063794, dual mTORC1/mTORC2 kinase inhibitors; and everolimus, allosteric mTORC1 inhibitor.
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pone.0131400.g001: Schematic representation of a network of PI3K/AKT/mTOR signaling.Inhibitors targeting the pathways are used in this study. Blue arrows and black lines represent activating and inhibitory connections, respectively. GDC-0941, pan-PI3K inhibitor; BEZ235 and GSK2126458, dual PI3K/mTOR kinase inhibitors; AZD8055, AZD82014 and KU-0063794, dual mTORC1/mTORC2 kinase inhibitors; and everolimus, allosteric mTORC1 inhibitor.

Mentions: We have chosen everolimus to address the question of whether anti-proliferative activity is related to inhibition of the mTOR signaling pathway, as measured by p70S6K phosphorylation. We have utilized 30 human breast cancer cell lines, including those that could be classified as ER and PR positive, HER2 over-expressing, or “triple negative”. We have also investigated whether the dual PI3K/mTOR inhibitors BEZ235 and GSK2126458, or the dual mTORC1/mTORC2 inhibitor (AZD8055), can sensitize everolimus resistant breast cancer cell lines to everolimus by reducing AKT phosphorylation. We selected four everolimus resistant triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-436, BT20 and HCC1143) to answer the question of whether ATP competitive mTORC1/2 inhibitors synergize with everolimus in their effects on cell proliferation. We have tested for possible interactions between everolimus and both dual PI3K/mTOR inhibitors and the pan-PI3K inhibitor GDC-0941 (Fig 1). These experiments help to answer the important question of whether combination therapy can overcome everolimus resistance.


Potentiation of Growth Inhibitory Responses of the mTOR Inhibitor Everolimus by Dual mTORC1/2 Inhibitors in Cultured Breast Cancer Cell Lines.

Leung EY, Askarian-Amiri M, Finlay GJ, Rewcastle GW, Baguley BC - PLoS ONE (2015)

Schematic representation of a network of PI3K/AKT/mTOR signaling.Inhibitors targeting the pathways are used in this study. Blue arrows and black lines represent activating and inhibitory connections, respectively. GDC-0941, pan-PI3K inhibitor; BEZ235 and GSK2126458, dual PI3K/mTOR kinase inhibitors; AZD8055, AZD82014 and KU-0063794, dual mTORC1/mTORC2 kinase inhibitors; and everolimus, allosteric mTORC1 inhibitor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492962&req=5

pone.0131400.g001: Schematic representation of a network of PI3K/AKT/mTOR signaling.Inhibitors targeting the pathways are used in this study. Blue arrows and black lines represent activating and inhibitory connections, respectively. GDC-0941, pan-PI3K inhibitor; BEZ235 and GSK2126458, dual PI3K/mTOR kinase inhibitors; AZD8055, AZD82014 and KU-0063794, dual mTORC1/mTORC2 kinase inhibitors; and everolimus, allosteric mTORC1 inhibitor.
Mentions: We have chosen everolimus to address the question of whether anti-proliferative activity is related to inhibition of the mTOR signaling pathway, as measured by p70S6K phosphorylation. We have utilized 30 human breast cancer cell lines, including those that could be classified as ER and PR positive, HER2 over-expressing, or “triple negative”. We have also investigated whether the dual PI3K/mTOR inhibitors BEZ235 and GSK2126458, or the dual mTORC1/mTORC2 inhibitor (AZD8055), can sensitize everolimus resistant breast cancer cell lines to everolimus by reducing AKT phosphorylation. We selected four everolimus resistant triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-436, BT20 and HCC1143) to answer the question of whether ATP competitive mTORC1/2 inhibitors synergize with everolimus in their effects on cell proliferation. We have tested for possible interactions between everolimus and both dual PI3K/mTOR inhibitors and the pan-PI3K inhibitor GDC-0941 (Fig 1). These experiments help to answer the important question of whether combination therapy can overcome everolimus resistance.

Bottom Line: We then carried out combination studies with four everolimus resistant triple-negative breast cancer cell lines, and found an unexpectedly high degree of synergy between everolimus and the other inhibitors tested.The level of potentiation of everolimus inhibitory activity (measured by IC50 values) was found to be cell line-specific for all the kinase inhibitors tested.The results suggest that judicious combination of mTOR inhibitors with different modes of action could have beneficial effects in the treatment of breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Auckland Cancer Society Research Centre, University of Auckland, Grafton, Auckland, New Zealand; Department of Molecular Medicine and Pathology, University of Auckland, Grafton, Auckland, New Zealand.

ABSTRACT
The mammalian target of rapamycin (mTOR), a vital component of signaling pathways involving PI3K/AKT, is an attractive therapeutic target in breast cancer. Everolimus, an allosteric mTOR inhibitor that inhibits the mTOR functional complex mTORC1, is approved for treatment of estrogen receptor positive (ER+) breast cancer. Other mTOR inhibitors show interesting differences in target specificities: BEZ235 and GSK2126458 are ATP competitive mTOR inhibitors targeting both PI3K and mTORC1/2; AZD8055, AZD2014 and KU-0063794 are ATP competitive mTOR inhibitors targeting both mTORC1 and mTORC2; and GDC-0941 is a pan-PI3K inhibitor. We have addressed the question of whether mTOR inhibitors may be more effective in combination than singly in inhibiting the proliferation of breast cancer cells. We selected a panel of 30 human breast cancer cell lines that included ER and PR positive, HER2 over-expressing, and "triple negative" variants, and determined whether signaling pathway utilization was related to drug-induced inhibition of proliferation. A significant correlation (p = 0.005) was found between everolimus IC50 values and p70S6K phosphorylation, but not with AKT or ERK phosphorylation, consistent with the mTOR pathway being a principal target. We then carried out combination studies with four everolimus resistant triple-negative breast cancer cell lines, and found an unexpectedly high degree of synergy between everolimus and the other inhibitors tested. The level of potentiation of everolimus inhibitory activity (measured by IC50 values) was found to be cell line-specific for all the kinase inhibitors tested. The results suggest that judicious combination of mTOR inhibitors with different modes of action could have beneficial effects in the treatment of breast cancer.

No MeSH data available.


Related in: MedlinePlus