A PI3K p110α-selective inhibitor enhances the efficacy of anti-HER2/neu antibody therapy against breast cancer in mice

Jae Hyeog Choi, Ki Hyang Kim, Kug Hwan Roh, Hana Jung, Anbok Lee, Ji Young Lee, Joo Yeon Song, Seung Jae Park, Ilhwan Kim, Won Sik Lee, Su Kil Seo, Il Whan Choi, Yang Xin Fu, Sung Su Yea, Sae Gwang Park

Research output: Contribution to journalArticle

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Abstract

Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-human epidermal growth factor receptor [HER]2/neu antibody) are effective against HER2+ breast cancer. Isoform-selective PI3K inhibitors elicit anti-tumor immune responses that are distinct from those induced by inhibitors of class I PI3K isoforms (pan-PI3K inhibitors). The present study investigated the therapeutic effect and potential for stimulating anti-tumor immunity of combined therapy with an anti-HER2/neu antibody and pan-PI3K inhibitor (GDC-0941) or a PI3K p110α isoform-selective inhibitor (A66) in mouse models of breast cancer. The anti-neu antibody inhibited tumor growth and enhanced anti-tumor immunity in HER2/neu+ breast cancer TUBO models, whereas GDC-0941 or A66 alone did not. Anti-neu antibody and PI3K inhibitor synergistically promoted anti-tumor immunity by increasing functional T cell production. In the presence of the anti-neu antibody, A66 was more effective than GDC-0941 at increasing the fraction of CD4+, CD8+, and IFN-γ+CD8+ T cells in the tumor-infiltrating lymphocyte population. Detection of IFN-γ levels by enzyme-linked immunospot assay showed that the numbers of tumor-specific T cells against neu and non-neu tumor antigens were increased by combined PI3K inhibitor plus anti-neu antibody treatment, with A66 exhibiting more potent effects than GDC-0941. In a TUBO (neu+) and TUBO-P2J (neu−) mixed tumor model representing immunohistochemistry 2+ tumors, A66 suppressed tumor growth and prolonged survival to a greater extent than GDC-0941 when combined with anti-neu antibody. These results demonstrate that a PI3K p110α-isoform-selective inhibitor is an effective adjunct to trastuzumab in the treatment of HER2-positive breast cancer.

Original languageEnglish (US)
JournalOncoImmunology
DOIs
StateAccepted/In press - Jan 12 2018

Fingerprint

1-Phosphatidylinositol 4-Kinase
Breast Neoplasms
Antibodies
Anti-Idiotypic Antibodies
Neoplasms
Protein Isoforms
Immunity
Therapeutics
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Enzyme-Linked Immunospot Assay
Neoplasm Antigens
Therapeutic Uses
Growth
Immunohistochemistry
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine

Keywords

  • anti-HER2/neu antibody
  • anti-tumor immunity
  • breast cancer
  • PI3K, p110α-selective inhibitor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

A PI3K p110α-selective inhibitor enhances the efficacy of anti-HER2/neu antibody therapy against breast cancer in mice. / Choi, Jae Hyeog; Kim, Ki Hyang; Roh, Kug Hwan; Jung, Hana; Lee, Anbok; Lee, Ji Young; Song, Joo Yeon; Park, Seung Jae; Kim, Ilhwan; Lee, Won Sik; Seo, Su Kil; Choi, Il Whan; Fu, Yang Xin; Yea, Sung Su; Park, Sae Gwang.

In: OncoImmunology, 12.01.2018.

Research output: Contribution to journalArticle

Choi, JH, Kim, KH, Roh, KH, Jung, H, Lee, A, Lee, JY, Song, JY, Park, SJ, Kim, I, Lee, WS, Seo, SK, Choi, IW, Fu, YX, Yea, SS & Park, SG 2018, 'A PI3K p110α-selective inhibitor enhances the efficacy of anti-HER2/neu antibody therapy against breast cancer in mice', OncoImmunology. https://doi.org/10.1080/2162402X.2017.1421890
Choi, Jae Hyeog ; Kim, Ki Hyang ; Roh, Kug Hwan ; Jung, Hana ; Lee, Anbok ; Lee, Ji Young ; Song, Joo Yeon ; Park, Seung Jae ; Kim, Ilhwan ; Lee, Won Sik ; Seo, Su Kil ; Choi, Il Whan ; Fu, Yang Xin ; Yea, Sung Su ; Park, Sae Gwang. / A PI3K p110α-selective inhibitor enhances the efficacy of anti-HER2/neu antibody therapy against breast cancer in mice. In: OncoImmunology. 2018.
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AU - Song, Joo Yeon

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AU - Kim, Ilhwan

AU - Lee, Won Sik

AU - Seo, Su Kil

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AU - Yea, Sung Su

AU - Park, Sae Gwang

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AB - Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-human epidermal growth factor receptor [HER]2/neu antibody) are effective against HER2+ breast cancer. Isoform-selective PI3K inhibitors elicit anti-tumor immune responses that are distinct from those induced by inhibitors of class I PI3K isoforms (pan-PI3K inhibitors). The present study investigated the therapeutic effect and potential for stimulating anti-tumor immunity of combined therapy with an anti-HER2/neu antibody and pan-PI3K inhibitor (GDC-0941) or a PI3K p110α isoform-selective inhibitor (A66) in mouse models of breast cancer. The anti-neu antibody inhibited tumor growth and enhanced anti-tumor immunity in HER2/neu+ breast cancer TUBO models, whereas GDC-0941 or A66 alone did not. Anti-neu antibody and PI3K inhibitor synergistically promoted anti-tumor immunity by increasing functional T cell production. In the presence of the anti-neu antibody, A66 was more effective than GDC-0941 at increasing the fraction of CD4+, CD8+, and IFN-γ+CD8+ T cells in the tumor-infiltrating lymphocyte population. Detection of IFN-γ levels by enzyme-linked immunospot assay showed that the numbers of tumor-specific T cells against neu and non-neu tumor antigens were increased by combined PI3K inhibitor plus anti-neu antibody treatment, with A66 exhibiting more potent effects than GDC-0941. In a TUBO (neu+) and TUBO-P2J (neu−) mixed tumor model representing immunohistochemistry 2+ tumors, A66 suppressed tumor growth and prolonged survival to a greater extent than GDC-0941 when combined with anti-neu antibody. These results demonstrate that a PI3K p110α-isoform-selective inhibitor is an effective adjunct to trastuzumab in the treatment of HER2-positive breast cancer.

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