title: PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors.
abstract: BACKGROUND
  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.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lehmann
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bauer
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Schafer
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Pendleton
authors.forename: Luojia
authors.initials: L
authors.lastname: Tang
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Johnson
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.forename: Henry
authors.initials: H
authors.lastname: Gómez
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D016000:Cluster Analysis; D013196:Dihydrotestosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D013196:Dihydrotestosterone; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D058570:TOR Serine-Threonine Kinases; C410798:AR protein, human; C484760:PIK3CA protein, human
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