PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors

Brian D. Lehmann, Joshua A. Bauer, Johanna M. Schafer, Christopher S. Pendleton, Luojia Tang, Kimberly C. Johnson, Xi Chen, Justin M. Balko, Henry Gómez, Carlos L. Arteaga, Gordon Mills, Melinda E. Sanders, Jennifer A. Pietenpol

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

Introduction: Triple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses the androgen receptor (AR+). TNBC cells derived from these luminal AR + tumors have high frequency phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. The purpose of this study was to determine if targeting phosphoinositide 3-kinase (PI3K) alone or in combination with an AR antagonist is effective in AR + TNBC. Methods: We determined the frequency of activating PIK3CA mutations in AR + and AR- TNBC clinical cases. Using AR + TNBC cell line and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability. Results: PIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects. Conclusions: While approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with AR + TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR + TNBC; and, we show that the growth and viability of AR + TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors.

Original languageEnglish (US)
Article number406
JournalBreast Cancer Research
Volume16
Issue number4
DOIs
StatePublished - Aug 8 2014
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
1-Phosphatidylinositol 4-Kinase
Androgen Receptors
Mutation
Heterografts
Neoplasms
Growth
Cell Line
Adjuvant Chemotherapy
Standard of Care

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. / Lehmann, Brian D.; Bauer, Joshua A.; Schafer, Johanna M.; Pendleton, Christopher S.; Tang, Luojia; Johnson, Kimberly C.; Chen, Xi; Balko, Justin M.; Gómez, Henry; Arteaga, Carlos L.; Mills, Gordon; Sanders, Melinda E.; Pietenpol, Jennifer A.

In: Breast Cancer Research, Vol. 16, No. 4, 406, 08.08.2014.

Research output: Contribution to journalArticle

Lehmann, BD, Bauer, JA, Schafer, JM, Pendleton, CS, Tang, L, Johnson, KC, Chen, X, Balko, JM, Gómez, H, Arteaga, CL, Mills, G, Sanders, ME & Pietenpol, JA 2014, 'PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors', Breast Cancer Research, vol. 16, no. 4, 406. https://doi.org/10.1186/s13058-014-0406-x
Lehmann, Brian D. ; Bauer, Joshua A. ; Schafer, Johanna M. ; Pendleton, Christopher S. ; Tang, Luojia ; Johnson, Kimberly C. ; Chen, Xi ; Balko, Justin M. ; Gómez, Henry ; Arteaga, Carlos L. ; Mills, Gordon ; Sanders, Melinda E. ; Pietenpol, Jennifer A. / PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. In: Breast Cancer Research. 2014 ; Vol. 16, No. 4.
@article{f60a9306670942da9059f38e919d5cb1,
title = "PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors",
abstract = "Introduction: Triple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses the androgen receptor (AR+). TNBC cells derived from these luminal AR + tumors have high frequency phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. The purpose of this study was to determine if targeting phosphoinositide 3-kinase (PI3K) alone or in combination with an AR antagonist is effective in AR + TNBC. Methods: We determined the frequency of activating PIK3CA mutations in AR + and AR- TNBC clinical cases. Using AR + TNBC cell line and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability. Results: PIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40{\%} vs. 4{\%}), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects. Conclusions: While approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with AR + TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR + TNBC; and, we show that the growth and viability of AR + TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors.",
author = "Lehmann, {Brian D.} and Bauer, {Joshua A.} and Schafer, {Johanna M.} and Pendleton, {Christopher S.} and Luojia Tang and Johnson, {Kimberly C.} and Xi Chen and Balko, {Justin M.} and Henry G{\'o}mez and Arteaga, {Carlos L.} and Gordon Mills and Sanders, {Melinda E.} and Pietenpol, {Jennifer A.}",
year = "2014",
month = "8",
day = "8",
doi = "10.1186/s13058-014-0406-x",
language = "English (US)",
volume = "16",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",
number = "4",

}

TY - JOUR

T1 - PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors

AU - Lehmann, Brian D.

AU - Bauer, Joshua A.

AU - Schafer, Johanna M.

AU - Pendleton, Christopher S.

AU - Tang, Luojia

AU - Johnson, Kimberly C.

AU - Chen, Xi

AU - Balko, Justin M.

AU - Gómez, Henry

AU - Arteaga, Carlos L.

AU - Mills, Gordon

AU - Sanders, Melinda E.

AU - Pietenpol, Jennifer A.

PY - 2014/8/8

Y1 - 2014/8/8

N2 - Introduction: Triple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses the androgen receptor (AR+). TNBC cells derived from these luminal AR + tumors have high frequency phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. The purpose of this study was to determine if targeting phosphoinositide 3-kinase (PI3K) alone or in combination with an AR antagonist is effective in AR + TNBC. Methods: We determined the frequency of activating PIK3CA mutations in AR + and AR- TNBC clinical cases. Using AR + TNBC cell line and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability. Results: PIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects. Conclusions: While approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with AR + TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR + TNBC; and, we show that the growth and viability of AR + TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors.

AB - Introduction: Triple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses the androgen receptor (AR+). TNBC cells derived from these luminal AR + tumors have high frequency phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. The purpose of this study was to determine if targeting phosphoinositide 3-kinase (PI3K) alone or in combination with an AR antagonist is effective in AR + TNBC. Methods: We determined the frequency of activating PIK3CA mutations in AR + and AR- TNBC clinical cases. Using AR + TNBC cell line and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability. Results: PIK3CA kinase mutations were highly clonal, more frequent in AR + vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR + TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects. Conclusions: While approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with AR + TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR + TNBC; and, we show that the growth and viability of AR + TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=84919875495&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84919875495&partnerID=8YFLogxK

U2 - 10.1186/s13058-014-0406-x

DO - 10.1186/s13058-014-0406-x

M3 - Article

C2 - 25103565

AN - SCOPUS:84919875495

VL - 16

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 4

M1 - 406

ER -