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

• Published in: Oncoimmunology Vol. 7; no. 5; p. e1421890
• Main Authors: 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, SaeGwang
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 04.05.2018; Taylor & Francis Group
• Subjects: anti-HER2/neu antibody; anti-tumor immunity; breast cancer; Original Research; PI3K, p110α-selective inhibitor; anti-HER2/neu antibody; breast cancer; PI3K, p110α-selective inhibitor; anti-tumor immunity
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2017.1421890

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.