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

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 Heiser, Pavana Anur, Paul Spellman, Sylvie M. Guichard, Paul D. SmithBarry R. Davies, Teresa Klinowska, Adrian V. Lee, Gordon Mills, Mothaffar F. Rimawi, Susan G. Hilsenbeck, Joe Gray, Amit Joshi, C. K. Osborne, Rachel Schiff

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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.

Original languageEnglish (US)
Article number430
JournalBreast Cancer Research
Volume16
Issue number5
DOIs
StatePublished - Sep 11 2014

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TOR Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
Mitogen-Activated Protein Kinase Kinases
Phosphatidylinositol 3-Kinase
Phosphoric Monoester Hydrolases
Estrogen Receptors
Breast Neoplasms
Phosphotransferases
Therapeutics
Tensins
Heterografts
Apoptosis
Ligands
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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, Xiaoyong; Creighton, Chad J.; Biswal, Nrusingh C.; Kumar, Vijetha; Shea, Martin; Herrera, Sabrina; Contreras, Alejandro; Gutierrez, Carolina; Wang, Tao; Nanda, Sarmistha; Giuliano, Mario; Morrison, Gladys; Nardone, Agostina; Karlin, Kristen L.; Westbrook, Thomas F.; Heiser, Laura; Anur, Pavana; Spellman, Paul; Guichard, Sylvie M.; Smith, Paul D.; Davies, Barry R.; Klinowska, Teresa; Lee, Adrian V.; Mills, Gordon; Rimawi, Mothaffar F.; Hilsenbeck, Susan G.; Gray, Joe; Joshi, Amit; Osborne, C. K.; Schiff, Rachel.

In: Breast Cancer Research, Vol. 16, No. 5, 430, 11.09.2014.

Research output: Contribution to journalArticle

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, L, Anur, P, Spellman, P, Guichard, SM, Smith, PD, Davies, BR, Klinowska, T, Lee, AV, Mills, G, Rimawi, MF, Hilsenbeck, SG, Gray, J, Joshi, A, Osborne, CK & 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, vol. 16, no. 5, 430. https://doi.org/10.1186/s13058-014-0430-x
Fu, Xiaoyong ; Creighton, Chad J. ; Biswal, Nrusingh C. ; Kumar, Vijetha ; Shea, Martin ; Herrera, Sabrina ; Contreras, Alejandro ; Gutierrez, Carolina ; Wang, Tao ; Nanda, Sarmistha ; Giuliano, Mario ; Morrison, Gladys ; Nardone, Agostina ; Karlin, Kristen L. ; Westbrook, Thomas F. ; Heiser, Laura ; Anur, Pavana ; Spellman, Paul ; Guichard, Sylvie M. ; Smith, Paul D. ; Davies, Barry R. ; Klinowska, Teresa ; Lee, Adrian V. ; Mills, Gordon ; Rimawi, Mothaffar F. ; Hilsenbeck, Susan G. ; Gray, Joe ; Joshi, Amit ; Osborne, C. K. ; Schiff, Rachel. / 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. In: Breast Cancer Research. 2014 ; Vol. 16, No. 5.
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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.",
author = "Xiaoyong Fu and Creighton, {Chad J.} and Biswal, {Nrusingh C.} and Vijetha Kumar and Martin Shea and Sabrina Herrera and Alejandro Contreras and Carolina Gutierrez and Tao Wang and Sarmistha Nanda and Mario Giuliano and Gladys Morrison and Agostina Nardone and Karlin, {Kristen L.} and Westbrook, {Thomas F.} and Laura Heiser and Pavana Anur and Paul Spellman and Guichard, {Sylvie M.} and Smith, {Paul D.} and Davies, {Barry R.} and Teresa Klinowska and Lee, {Adrian V.} and Gordon Mills and Rimawi, {Mothaffar F.} and Hilsenbeck, {Susan G.} and Joe Gray and Amit Joshi and Osborne, {C. K.} and Rachel Schiff",
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T1 - 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

AU - Fu, Xiaoyong

AU - Creighton, Chad J.

AU - Biswal, Nrusingh C.

AU - Kumar, Vijetha

AU - Shea, Martin

AU - Herrera, Sabrina

AU - Contreras, Alejandro

AU - Gutierrez, Carolina

AU - Wang, Tao

AU - Nanda, Sarmistha

AU - Giuliano, Mario

AU - Morrison, Gladys

AU - Nardone, Agostina

AU - Karlin, Kristen L.

AU - Westbrook, Thomas F.

AU - Heiser, Laura

AU - Anur, Pavana

AU - Spellman, Paul

AU - Guichard, Sylvie M.

AU - Smith, Paul D.

AU - Davies, Barry R.

AU - Klinowska, Teresa

AU - Lee, Adrian V.

AU - Mills, Gordon

AU - Rimawi, Mothaffar F.

AU - Hilsenbeck, Susan G.

AU - Gray, Joe

AU - Joshi, Amit

AU - Osborne, C. K.

AU - Schiff, Rachel

PY - 2014/9/11

Y1 - 2014/9/11

N2 - 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.

AB - 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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DO - 10.1186/s13058-014-0430-x

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