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

被引:8
作者
Choi, Jae-Hyeog [1 ]
Kim, Ki Hyang [2 ]
Roh, Kug-Hwan [1 ]
Jung, Hana [1 ]
Lee, Anbok [3 ]
Lee, Ji-Young [2 ]
Song, Joo Yeon [5 ]
Park, Seung Jae [2 ]
Kim, Ilhwan [2 ]
Lee, Won-Sik [2 ]
Seo, Su-Kil [1 ]
Choi, Il-Whan [1 ]
Fu, Yang-Xin [6 ]
Yea, Sung Su [4 ]
Park, SaeGwang [1 ]
机构
[1] Inje Univ, Coll Med, Dept Microbiol & Immunol, Busan 47392, South Korea
[2] Inje Univ, Coll Med, Dept Internal Med, Busan, South Korea
[3] Inje Univ, Coll Med, Dept Surg, Busan, South Korea
[4] Inje Univ, Coll Med, Dept Biochem, Busan 47392, South Korea
[5] Dongnam Inst Radiol & Med Sci, Dept Pathol, Busan, South Korea
[6] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol & Immunol, Dallas, TX 75390 USA
来源
ONCOIMMUNOLOGY | 2018年 / 7卷 / 05期
基金
新加坡国家研究基金会;
关键词
PI3K; p110 alpha-selective inhibitor; anti-HER2/neu antibody; breast cancer; anti-tumor immunity; PHASE-I; TRASTUZUMAB; CARCINOMAS; RESISTANCE; GDC-0941; ISOFORMS; PATHWAY; COMPLEX; SAFETY; POTENT;
D O I
10.1080/2162402X.2017.1421890
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 p110 alpha 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-gamma(+)CD8(+) T cells in the tumor-infiltrating lymphocyte population. Detection of IFN-gamma 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 p110 alpha-isoform-selective inhibitor is an effective adjunct to trastuzumab in the treatment of HER2-positive breast cancer.
引用
收藏
页数:10
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