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

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1 Scopus citations

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)
Article numbere1421890
JournalOncoImmunology
Volume7
Issue number5
DOIs
StatePublished - May 4 2018

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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    Choi, J. H., Kim, K. H., Roh, K. H., Jung, H., Lee, A., Lee, J. Y., Song, J. Y., Park, S. J., Kim, I., Lee, W. S., Seo, S. K., Choi, I. W., Fu, Y. X., Yea, S. S., & Park, S. G. (2018). A PI3K p110α-selective inhibitor enhances the efficacy of anti-HER2/neu antibody therapy against breast cancer in mice. OncoImmunology, 7(5), [e1421890]. https://doi.org/10.1080/2162402X.2017.1421890