title: Concomitant targeting of tumor cells and induction of T-cell response synergizes to effectively inhibit trastuzumab-resistant breast cancer.
abstract: Trastuzumab is an iconic rationally designed targeted therapy for HER2-positive breast cancers. However, the low response rate and development of resistance call for novel approaches for the treatment of patients. Here, we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct PTEN loss-mediated trastuzumab-resistant mammary tumor mouse models. In vivo combination treatment with HER2/Neu antibody and Akt inhibitor triciribine effectively inhibited tumor growth in both models via inhibiting PI3K/AKT and mitogen-activated protein kinase signaling accompanied by increased T-cell infiltration in the tumor microenvironment. We showed that both CD8(+) and CD4(+) T cells were essential to the optimal antitumor effect of this combination treatment in an IFN-γ-dependent manner. Importantly, the antitumor activities of HER2/Neu antibody and triciribine combination treatment were further improved when coinhibitory receptor cytotoxic T-lymphocyte-associated antigen 4 was blocked to enhance the T-cell response. Our data indicate that multitargeted combinatorial therapies targeting tumor cells and concomitantly enhancing T-cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity, suggesting a promising clinical strategy for treating trastuzumab-resistant breast cancers and other advanced malignancies.
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Qingfei
authors: Q
authors: Wang
authors: Shau-Hsuan
authors: SH
authors: Li
authors: Hai
authors: H
authors: Wang
authors: Yi
authors: Y
authors: Xiao
authors: Ozgur
authors: O
authors: Sahin
authors: Samuel W
authors: SW
authors: Brady
authors: Ping
authors: P
authors: Li
authors: Hailiang
authors: H
authors: Ge
authors: Elizabeth M
authors: EM
authors: Jaffee
authors: William J
authors: WJ
authors: Muller
authors: Gabriel N
authors: GN
authors: Hortobagyi
authors: Dihua
authors: D
authors: Yu
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D002460:Cell Line; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D012263:Ribonucleosides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D000068878:Trastuzumab; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D007371:Interferon-gamma; D051059:PTEN Phosphohydrolase; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D012263:Ribonucleosides; D000068878:Trastuzumab; C023764:triciribine