Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase.

Abstract

INTRODUCTION:

Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance.

METHODS:

Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.

RESULTS:

Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.

CONCLUSIONS:

Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.

• Authors: Xiaoyong Fu, Chad J Creighton, Nrusingh C Biswal, Vijetha Kumar, Martin Shea, Sabrina Herrera, Alejandro Contreras, Carolina Gutierrez, Tao Wang, Sarmistha Nanda, Mario Giuliano, Gladys Morrison, Agostina Nardone, Kristen L Karlin, Thomas F Westbrook, Laura M Heiser, Pavana Anur, Paul Spellman, Sylvie M Guichard, Paul D Smith, Barry R Davies, Teresa Klinowska, Adrian V Lee, Gordon B Mills, Mothaffar F Rimawi, Susan G Hilsenbeck, Joe W Gray, Amit Joshi, C Kent Osborne, Rachel Schiff
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 16 Issue 5 Pg. 430 (Sep 11 2014) ISSN: 1465-542X [Electronic] England
• PMID: 25212826 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Protein Kinase Inhibitors
• Receptors, Estrogen
• Tamoxifen
• Fulvestrant
• Estradiol
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases
• PTEN Phosphohydrolase
• PTEN protein, human
• Doxycycline
• Sirolimus

Topics

• Animals
• Antineoplastic Agents, Hormonal (pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Doxycycline (pharmacology)
• Drug Resistance, Neoplasm
• Estradiol (analogs & derivatives, pharmacology)
• Female
• Fulvestrant
• Gene Expression
• Gene Knockdown Techniques
• Humans
• MCF-7 Cells
• Mice, Nude
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Molecular Targeted Therapy
• Neoplasms, Hormone-Dependent (drug therapy, metabolism)
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Receptors, Estrogen (metabolism)
• Signal Transduction
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Tamoxifen (pharmacology)
• Xenograft Model Antitumor Assays