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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

Fu, X and Creighton, CJ and Biswal, NC and Kumar, V and Shea, M and Herrera, S and Contreras, A and Gutierrez, C and Wang, T and Nanda, S and Giuliano, M and Morrison, G and Nardone, A and Karlin, KL and Westbrook, TF and Heiser, LM and Anur, P and Spellman, P and Guichard, SM and Smith, PD and Davies, BR and Klinowska, T and Lee, AV and Mills, GB and Rimawi, MF and Hilsenbeck, SG and Gray, JW and Joshi, A and Osborne, CK and Schiff, R (2014) 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. Breast Cancer Research, 16 (5). ISSN 1465-5411

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Abstract

© 2014 Fu et al.; licensee BioMed Central Ltd. 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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Fu, X
Creighton, CJ
Biswal, NC
Kumar, V
Shea, M
Herrera, S
Contreras, A
Gutierrez, C
Wang, T
Nanda, S
Giuliano, M
Morrison, G
Nardone, A
Karlin, KL
Westbrook, TF
Heiser, LM
Anur, P
Spellman, P
Guichard, SM
Smith, PD
Davies, BR
Klinowska, T
Lee, AVavl10@pitt.eduAVL10
Mills, GB
Rimawi, MF
Hilsenbeck, SG
Gray, JW
Joshi, A
Osborne, CK
Schiff, R
Centers: Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute
Date: 11 September 2014
Date Type: Publication
Journal or Publication Title: Breast Cancer Research
Volume: 16
Number: 5
DOI or Unique Handle: 10.1186/s13058-014-0430-x
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
ISSN: 1465-5411
Date Deposited: 19 Sep 2016 15:51
Last Modified: 04 Feb 2019 15:58
URI: http://d-scholarship.pitt.edu/id/eprint/29493

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