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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

The growth inhibitory effects of drug combinations on MDA-MB-231, MDA-MB-436, BT20 and HCC1143 breast cancer cell lines.Growth inhibitory effects of combinations of everolimus with BEZ235 (BEZ) (left hand panel), GSK2126458 (GSK) (middle panel) and AZD8055 (AZD) (right hand panel) using the Bliss additivism method. Dashed line, Bliss additivity curve, representing the theoretical expectation if the combined effects of everolimus with kinase inhibitors were exactly additive. Averages of three independent experiments are shown.
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pone.0131400.g005: The growth inhibitory effects of drug combinations on MDA-MB-231, MDA-MB-436, BT20 and HCC1143 breast cancer cell lines.Growth inhibitory effects of combinations of everolimus with BEZ235 (BEZ) (left hand panel), GSK2126458 (GSK) (middle panel) and AZD8055 (AZD) (right hand panel) using the Bliss additivism method. Dashed line, Bliss additivity curve, representing the theoretical expectation if the combined effects of everolimus with kinase inhibitors were exactly additive. Averages of three independent experiments are shown.

Mentions: We measured the effects of combinations of everolimus and mTOR ATP competitive inhibitors (BEZ235, GSK2126458, or AZD8055) (Fig 5). The Bliss additivism model [26] was used to assess drug interactions; this method has an advantage over combination index analysis since it is possible to evaluate the nature of drug interactions even when the maximal inhibition by mTOR inhibitors as single agents is too low for a reliable IC50 value to be obtained. The model indicates synergy between everolimus and mTOR ATP competitive inhibitors for all lines tested (Fig 5).


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)

The growth inhibitory effects of drug combinations on MDA-MB-231, MDA-MB-436, BT20 and HCC1143 breast cancer cell lines.Growth inhibitory effects of combinations of everolimus with BEZ235 (BEZ) (left hand panel), GSK2126458 (GSK) (middle panel) and AZD8055 (AZD) (right hand panel) using the Bliss additivism method. Dashed line, Bliss additivity curve, representing the theoretical expectation if the combined effects of everolimus with kinase inhibitors were exactly additive. Averages of three independent experiments are shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131400.g005: The growth inhibitory effects of drug combinations on MDA-MB-231, MDA-MB-436, BT20 and HCC1143 breast cancer cell lines.Growth inhibitory effects of combinations of everolimus with BEZ235 (BEZ) (left hand panel), GSK2126458 (GSK) (middle panel) and AZD8055 (AZD) (right hand panel) using the Bliss additivism method. Dashed line, Bliss additivity curve, representing the theoretical expectation if the combined effects of everolimus with kinase inhibitors were exactly additive. Averages of three independent experiments are shown.
Mentions: We measured the effects of combinations of everolimus and mTOR ATP competitive inhibitors (BEZ235, GSK2126458, or AZD8055) (Fig 5). The Bliss additivism model [26] was used to assess drug interactions; this method has an advantage over combination index analysis since it is possible to evaluate the nature of drug interactions even when the maximal inhibition by mTOR inhibitors as single agents is too low for a reliable IC50 value to be obtained. The model indicates synergy between everolimus and mTOR ATP competitive inhibitors for all lines tested (Fig 5).

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