PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer

Ana Bosch, Zhiqiang Li, Anna Bergamaschi, Haley Ellis, Eneda Toska, Aleix Prat, Jessica Tao, Daniel E. Spratt, Nerissa T. Viola-Villegas, Pau Castel, Gerard Minuesa, Natasha Morse, Jordi Rodón, Yasir Ibrahim, Javier Cortes, Jose Perez-Garcia, Patricia Galvan, Judit Grueso, Marta Guzman, John A. KatzenellenbogenMichaelz Kharas, Jason S. Lewis, Maura Dickler, Violeta Serra, Neal Rosen, Sarat Chandarlapaty, Maurizio Scaltriti, José Baselga

Research output: Contribution to journalArticle

Abstract

Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.

Original languageEnglish (US)
Article number283ra51
JournalScience translational medicine
Volume7
Issue number283
DOIs
StatePublished - Apr 15 2015
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Estrogen Receptors
Hormones
Breast Neoplasms
Neoplasms
Gene Expression
Tamoxifen
Heterografts
Genetic Promoter Regions
Estradiol
Binding Sites

ASJC Scopus subject areas

  • Medicine(all)

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PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. / Bosch, Ana; Li, Zhiqiang; Bergamaschi, Anna; Ellis, Haley; Toska, Eneda; Prat, Aleix; Tao, Jessica; Spratt, Daniel E.; Viola-Villegas, Nerissa T.; Castel, Pau; Minuesa, Gerard; Morse, Natasha; Rodón, Jordi; Ibrahim, Yasir; Cortes, Javier; Perez-Garcia, Jose; Galvan, Patricia; Grueso, Judit; Guzman, Marta; Katzenellenbogen, John A.; Kharas, Michaelz; Lewis, Jason S.; Dickler, Maura; Serra, Violeta; Rosen, Neal; Chandarlapaty, Sarat; Scaltriti, Maurizio; Baselga, José.

In: Science translational medicine, Vol. 7, No. 283, 283ra51, 15.04.2015.

Research output: Contribution to journalArticle

Bosch, A, Li, Z, Bergamaschi, A, Ellis, H, Toska, E, Prat, A, Tao, J, Spratt, DE, Viola-Villegas, NT, Castel, P, Minuesa, G, Morse, N, Rodón, J, Ibrahim, Y, Cortes, J, Perez-Garcia, J, Galvan, P, Grueso, J, Guzman, M, Katzenellenbogen, JA, Kharas, M, Lewis, JS, Dickler, M, Serra, V, Rosen, N, Chandarlapaty, S, Scaltriti, M & Baselga, J 2015, 'PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer', Science translational medicine, vol. 7, no. 283, 283ra51. https://doi.org/10.1126/scitranslmed.aaa4442
Bosch, Ana ; Li, Zhiqiang ; Bergamaschi, Anna ; Ellis, Haley ; Toska, Eneda ; Prat, Aleix ; Tao, Jessica ; Spratt, Daniel E. ; Viola-Villegas, Nerissa T. ; Castel, Pau ; Minuesa, Gerard ; Morse, Natasha ; Rodón, Jordi ; Ibrahim, Yasir ; Cortes, Javier ; Perez-Garcia, Jose ; Galvan, Patricia ; Grueso, Judit ; Guzman, Marta ; Katzenellenbogen, John A. ; Kharas, Michaelz ; Lewis, Jason S. ; Dickler, Maura ; Serra, Violeta ; Rosen, Neal ; Chandarlapaty, Sarat ; Scaltriti, Maurizio ; Baselga, José. / PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. In: Science translational medicine. 2015 ; Vol. 7, No. 283.
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abstract = "Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.",
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T1 - PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer

AU - Bosch, Ana

AU - Li, Zhiqiang

AU - Bergamaschi, Anna

AU - Ellis, Haley

AU - Toska, Eneda

AU - Prat, Aleix

AU - Tao, Jessica

AU - Spratt, Daniel E.

AU - Viola-Villegas, Nerissa T.

AU - Castel, Pau

AU - Minuesa, Gerard

AU - Morse, Natasha

AU - Rodón, Jordi

AU - Ibrahim, Yasir

AU - Cortes, Javier

AU - Perez-Garcia, Jose

AU - Galvan, Patricia

AU - Grueso, Judit

AU - Guzman, Marta

AU - Katzenellenbogen, John A.

AU - Kharas, Michaelz

AU - Lewis, Jason S.

AU - Dickler, Maura

AU - Serra, Violeta

AU - Rosen, Neal

AU - Chandarlapaty, Sarat

AU - Scaltriti, Maurizio

AU - Baselga, José

PY - 2015/4/15

Y1 - 2015/4/15

N2 - Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.

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