Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells
Euphemia Leung, Ji Eun Kim, Gordon W Rewcastle, Graeme J Finlay, Bruce C Baguley, Euphemia Leung, Ji Eun Kim, Gordon W Rewcastle, Graeme J Finlay, Bruce C Baguley
Abstract
Background: Treatment with anti-estrogens or aromatase inhibitors is commonly used for patients with estrogen receptor-positive (ER+) breast cancers; however resistant disease develops almost inevitably, requiring a choice of secondary therapy. One possibility is to use inhibitors of the PI3K/mTOR pathway and several candidate drugs are in development. We examined the in vitro effects of two inhibitors of the PI3K/mTOR pathway on resistant MCF-7 cells.
Methods: We cultured MCF-7 cells for prolonged periods either in the presence of the anti-estrogen tamoxifen (3 sub-lines) or in estrogen free medium (2 sub-lines) to mimic the effects of clinical treatment. We then analyzed the effects of two dual PI3K/mTOR phosphoinositide-3-kinase inhibitors, NVP-BEZ235 and GSK2126458, on the growth and signaling pathways of these MCF-7 sub-lines. The functional status of the PI3K, mTOR and ERK pathways was analyzed by measuring phosphorylation of AKT, p70S6K, rpS6 and ERK.
Results: The derived sub-lines showed increased resistance to tamoxifen but none exhibited concomitantly increased sensitivity to the PI3K inhibitors. NVP-BEZ235 and GSK2126458 acted mainly by induction of cell cycle arrest, particularly in G1-phase, rather than by induction of apoptosis. The lines varied considerably in their utilization of the AKT, p70S6K and ERK pathways. NVP-BEZ235 and GSK2126458 inhibited AKT signaling but NVP-BEZ235 showed greater effects than GSK2126458 on p70S6K and rpS6 signaling with effects resembling those of rapamycin.
Conclusion: Increased resistance to tamoxifen in these MCF-7 sub-lines is not associated with hypersensitivity to PI3K inhibitors. While both drugs inhibited AKT signaling, NVP-BEZ235 resembled rapamycin in inhibiting the mTOR pathway.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3127046/bin/cbt1111_0938_fig001.jpg)
Figure 2
G 1 /S cell cycle…
Figure 2
G 1 /S cell cycle arrest in MCF-7 cell lines treated with indicated…
Figure 3
Immunoblotting for PI3K pathway signaling…
Figure 3
Immunoblotting for PI3K pathway signaling proteins in MCF-7 cell lines treated with different…
Figure 3
Immunoblotting for PI3K pathway signaling…
Figure 3
Immunoblotting for PI3K pathway signaling proteins in MCF-7 cell lines treated with different…
Figure 4
Immunoblotting for p-Akt(S473) and ER…
Figure 4
Immunoblotting for p-Akt(S473) and ER antibodies. MCF-7 sub-lines were treated with the indicated…
- Overcoming resistance: targeting the PI3K/mTOR pathway in endocrine refractory breast cancer.Butt AJ. Butt AJ. Cancer Biol Ther. 2011 Jun 1;11(11):947-9. doi: 10.4161/cbt.11.11.15953. Epub 2011 Jun 1. Cancer Biol Ther. 2011. PMID: 21577052 No abstract available.
- Relationships between signaling pathway usage and sensitivity to a pathway inhibitor: examination of trametinib responses in cultured breast cancer lines.Leung EY, Kim JE, Askarian-Amiri M, Rewcastle GW, Finlay GJ, Baguley BC. Leung EY, et al. PLoS One. 2014 Aug 29;9(8):e105792. doi: 10.1371/journal.pone.0105792. eCollection 2014. PLoS One. 2014. PMID: 25170609 Free PMC article.
- NVP-BEZ235, a novel dual PI3K-mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells.Yu Z, Xie G, Zhou G, Cheng Y, Zhang G, Yao G, Chen Y, Li Y, Zhao G. Yu Z, et al. Cancer Lett. 2015 Oct 10;367(1):58-68. doi: 10.1016/j.canlet.2015.07.007. Epub 2015 Jul 15. Cancer Lett. 2015. PMID: 26188279
- Inhibition of Autophagy Increases Proliferation Inhibition and Apoptosis Induced by the PI3K/mTOR Inhibitor NVP-BEZ235 in Breast Cancer Cells.Ji Y, Di W, Yang Q, Lu Z, Cai W, Wu J. Ji Y, et al. Clin Lab. 2015;61(8):1043-51. doi: 10.7754/clin.lab.2015.150144. Clin Lab. 2015. PMID: 26427150
- Targeting the PI3K/AKT/mTOR Pathway in Hormone-Positive Breast Cancer.Nunnery SE, Mayer IA. Nunnery SE, et al. Drugs. 2020 Nov;80(16):1685-1697. doi: 10.1007/s40265-020-01394-w. Drugs. 2020. PMID: 32894420 Free PMC article. Review.
- Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway.Burris HA 3rd. Burris HA 3rd. Cancer Chemother Pharmacol. 2013 Apr;71(4):829-42. doi: 10.1007/s00280-012-2043-3. Epub 2013 Feb 3. Cancer Chemother Pharmacol. 2013. PMID: 23377372 Review.
- Comparative Study
- Research Support, Non-U.S. Gov't
- Antineoplastic Agents, Hormonal / pharmacology*
- Breast Neoplasms / metabolism
- Breast Neoplasms / pathology*
- Cell Line, Tumor
- Cell Proliferation / drug effects
- Drug Resistance, Neoplasm / drug effects*
- Extracellular Signal-Regulated MAP Kinases / metabolism
- Female
- G1 Phase / drug effects
- Humans
- Imidazoles / pharmacology*
- Neoplasms, Hormone-Dependent / metabolism
- Neoplasms, Hormone-Dependent / pathology*
- Phosphoinositide-3 Kinase Inhibitors*
- Phosphorylation
- Poly(ADP-ribose) Polymerases / metabolism
- Proto-Oncogene Proteins c-akt / metabolism
- Pyridazines
- Quinolines / pharmacology*
- Receptors, Estrogen / metabolism
- Ribosomal Protein S6 / metabolism
- Sulfonamides / pharmacology*
- TOR Serine-Threonine Kinases / antagonists & inhibitors*
- Tamoxifen / pharmacology*
- Antineoplastic Agents, Hormonal
- Imidazoles
- Phosphoinositide-3 Kinase Inhibitors
- Pyridazines
- Quinolines
- Receptors, Estrogen
- Ribosomal Protein S6
- Sulfonamides
- Tamoxifen
- omipalisib
- Poly(ADP-ribose) Polymerases
- MTOR protein, human
- Proto-Oncogene Proteins c-akt
- TOR Serine-Threonine Kinases
- Extracellular Signal-Regulated MAP Kinases
- dactolisib
- Full Text Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3127046/bin/cbt1111_0938_fig002.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3127046/bin/cbt1111_0938_fig003a.jpg)
Figure 3
Immunoblotting for PI3K pathway signaling…
Figure 3
Immunoblotting for PI3K pathway signaling proteins in MCF-7 cell lines treated with different…
Figure 4
Immunoblotting for p-Akt(S473) and ER…
Figure 4
Immunoblotting for p-Akt(S473) and ER antibodies. MCF-7 sub-lines were treated with the indicated…
- Overcoming resistance: targeting the PI3K/mTOR pathway in endocrine refractory breast cancer.Butt AJ. Butt AJ. Cancer Biol Ther. 2011 Jun 1;11(11):947-9. doi: 10.4161/cbt.11.11.15953. Epub 2011 Jun 1. Cancer Biol Ther. 2011. PMID: 21577052 No abstract available.
- Relationships between signaling pathway usage and sensitivity to a pathway inhibitor: examination of trametinib responses in cultured breast cancer lines.Leung EY, Kim JE, Askarian-Amiri M, Rewcastle GW, Finlay GJ, Baguley BC. Leung EY, et al. PLoS One. 2014 Aug 29;9(8):e105792. doi: 10.1371/journal.pone.0105792. eCollection 2014. PLoS One. 2014. PMID: 25170609 Free PMC article.
- NVP-BEZ235, a novel dual PI3K-mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells.Yu Z, Xie G, Zhou G, Cheng Y, Zhang G, Yao G, Chen Y, Li Y, Zhao G. Yu Z, et al. Cancer Lett. 2015 Oct 10;367(1):58-68. doi: 10.1016/j.canlet.2015.07.007. Epub 2015 Jul 15. Cancer Lett. 2015. PMID: 26188279
- Inhibition of Autophagy Increases Proliferation Inhibition and Apoptosis Induced by the PI3K/mTOR Inhibitor NVP-BEZ235 in Breast Cancer Cells.Ji Y, Di W, Yang Q, Lu Z, Cai W, Wu J. Ji Y, et al. Clin Lab. 2015;61(8):1043-51. doi: 10.7754/clin.lab.2015.150144. Clin Lab. 2015. PMID: 26427150
- Targeting the PI3K/AKT/mTOR Pathway in Hormone-Positive Breast Cancer.Nunnery SE, Mayer IA. Nunnery SE, et al. Drugs. 2020 Nov;80(16):1685-1697. doi: 10.1007/s40265-020-01394-w. Drugs. 2020. PMID: 32894420 Free PMC article. Review.
- Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway.Burris HA 3rd. Burris HA 3rd. Cancer Chemother Pharmacol. 2013 Apr;71(4):829-42. doi: 10.1007/s00280-012-2043-3. Epub 2013 Feb 3. Cancer Chemother Pharmacol. 2013. PMID: 23377372 Review.
- Comparative Study
- Research Support, Non-U.S. Gov't
- Antineoplastic Agents, Hormonal / pharmacology*
- Breast Neoplasms / metabolism
- Breast Neoplasms / pathology*
- Cell Line, Tumor
- Cell Proliferation / drug effects
- Drug Resistance, Neoplasm / drug effects*
- Extracellular Signal-Regulated MAP Kinases / metabolism
- Female
- G1 Phase / drug effects
- Humans
- Imidazoles / pharmacology*
- Neoplasms, Hormone-Dependent / metabolism
- Neoplasms, Hormone-Dependent / pathology*
- Phosphoinositide-3 Kinase Inhibitors*
- Phosphorylation
- Poly(ADP-ribose) Polymerases / metabolism
- Proto-Oncogene Proteins c-akt / metabolism
- Pyridazines
- Quinolines / pharmacology*
- Receptors, Estrogen / metabolism
- Ribosomal Protein S6 / metabolism
- Sulfonamides / pharmacology*
- TOR Serine-Threonine Kinases / antagonists & inhibitors*
- Tamoxifen / pharmacology*
- Antineoplastic Agents, Hormonal
- Imidazoles
- Phosphoinositide-3 Kinase Inhibitors
- Pyridazines
- Quinolines
- Receptors, Estrogen
- Ribosomal Protein S6
- Sulfonamides
- Tamoxifen
- omipalisib
- Poly(ADP-ribose) Polymerases
- MTOR protein, human
- Proto-Oncogene Proteins c-akt
- TOR Serine-Threonine Kinases
- Extracellular Signal-Regulated MAP Kinases
- dactolisib
- Full Text Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3127046/bin/cbt1111_0938_fig003b.jpg)
Figure 4
Immunoblotting for p-Akt(S473) and ER…
Figure 4
Immunoblotting for p-Akt(S473) and ER antibodies. MCF-7 sub-lines were treated with the indicated…
- Overcoming resistance: targeting the PI3K/mTOR pathway in endocrine refractory breast cancer.Butt AJ. Butt AJ. Cancer Biol Ther. 2011 Jun 1;11(11):947-9. doi: 10.4161/cbt.11.11.15953. Epub 2011 Jun 1. Cancer Biol Ther. 2011. PMID: 21577052 No abstract available.
- Relationships between signaling pathway usage and sensitivity to a pathway inhibitor: examination of trametinib responses in cultured breast cancer lines.Leung EY, Kim JE, Askarian-Amiri M, Rewcastle GW, Finlay GJ, Baguley BC. Leung EY, et al. PLoS One. 2014 Aug 29;9(8):e105792. doi: 10.1371/journal.pone.0105792. eCollection 2014. PLoS One. 2014. PMID: 25170609 Free PMC article.
- NVP-BEZ235, a novel dual PI3K-mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells.Yu Z, Xie G, Zhou G, Cheng Y, Zhang G, Yao G, Chen Y, Li Y, Zhao G. Yu Z, et al. Cancer Lett. 2015 Oct 10;367(1):58-68. doi: 10.1016/j.canlet.2015.07.007. Epub 2015 Jul 15. Cancer Lett. 2015. PMID: 26188279
- Inhibition of Autophagy Increases Proliferation Inhibition and Apoptosis Induced by the PI3K/mTOR Inhibitor NVP-BEZ235 in Breast Cancer Cells.Ji Y, Di W, Yang Q, Lu Z, Cai W, Wu J. Ji Y, et al. Clin Lab. 2015;61(8):1043-51. doi: 10.7754/clin.lab.2015.150144. Clin Lab. 2015. PMID: 26427150
- Targeting the PI3K/AKT/mTOR Pathway in Hormone-Positive Breast Cancer.Nunnery SE, Mayer IA. Nunnery SE, et al. Drugs. 2020 Nov;80(16):1685-1697. doi: 10.1007/s40265-020-01394-w. Drugs. 2020. PMID: 32894420 Free PMC article. Review.
- Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway.Burris HA 3rd. Burris HA 3rd. Cancer Chemother Pharmacol. 2013 Apr;71(4):829-42. doi: 10.1007/s00280-012-2043-3. Epub 2013 Feb 3. Cancer Chemother Pharmacol. 2013. PMID: 23377372 Review.
- Comparative Study
- Research Support, Non-U.S. Gov't
- Antineoplastic Agents, Hormonal / pharmacology*
- Breast Neoplasms / metabolism
- Breast Neoplasms / pathology*
- Cell Line, Tumor
- Cell Proliferation / drug effects
- Drug Resistance, Neoplasm / drug effects*
- Extracellular Signal-Regulated MAP Kinases / metabolism
- Female
- G1 Phase / drug effects
- Humans
- Imidazoles / pharmacology*
- Neoplasms, Hormone-Dependent / metabolism
- Neoplasms, Hormone-Dependent / pathology*
- Phosphoinositide-3 Kinase Inhibitors*
- Phosphorylation
- Poly(ADP-ribose) Polymerases / metabolism
- Proto-Oncogene Proteins c-akt / metabolism
- Pyridazines
- Quinolines / pharmacology*
- Receptors, Estrogen / metabolism
- Ribosomal Protein S6 / metabolism
- Sulfonamides / pharmacology*
- TOR Serine-Threonine Kinases / antagonists & inhibitors*
- Tamoxifen / pharmacology*
- Antineoplastic Agents, Hormonal
- Imidazoles
- Phosphoinositide-3 Kinase Inhibitors
- Pyridazines
- Quinolines
- Receptors, Estrogen
- Ribosomal Protein S6
- Sulfonamides
- Tamoxifen
- omipalisib
- Poly(ADP-ribose) Polymerases
- MTOR protein, human
- Proto-Oncogene Proteins c-akt
- TOR Serine-Threonine Kinases
- Extracellular Signal-Regulated MAP Kinases
- dactolisib
- Full Text Sources
- Medical
- Miscellaneous
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3127046/bin/cbt1111_0938_fig004.jpg)
Source: PubMed