Li and Sun et al. identified heterozygous 17ploss as common across breast cancer, and correlated with poor survival and low T cell infiltration and cytotoxicity in TNBC. Trastuzumab (targets HER2) conjugated to the POLR2A inhibitor α-amanitin (T-Ama; PolR2A is located on 17p) effectively killed 17plossHER2low breast cancer cell lines in vitro and controlled tumor burden in 17plossHER-2low xenograft and PDX models. α-Amanitin induced immunogenic cell death in cell lines, and vaccination with T-Ama-treated cells protected mice against tumor challenge. T-Ama plus anti-PD-1 showed infiltration of activated and cytotoxic CD8+ and CD4+ T cells and enhanced tumor control.
Contributed by Shishir Pant
ABSTRACT: The clinical challenge for treating HER2 (human epidermal growth factor receptor 2)-low breast cancer is the paucity of actionable drug targets. HER2-targeted therapy often has poor clinical efficacy for this disease due to the low level of HER2 protein on the cancer cell surface. We analyzed breast cancer genomics in the search for potential drug targets. Heterozygous loss of chromosome 17p is one of the most frequent genomic events in breast cancer, and 17p loss involves a massive deletion of genes including the tumor suppressor TP53 Our analyses revealed that 17p loss leads to global gene expression changes and reduced tumor infiltration and cytotoxicity of T cells, resulting in immune evasion during breast tumor progression. The 17p deletion region also includes POLR2A, a gene encoding the catalytic subunit of RNA polymerase II that is essential for cell survival. Therefore, breast cancer cells with heterozygous loss of 17p are extremely sensitive to the inhibition of POLR2A via a specific small-molecule inhibitor, α-amanitin. Here, we demonstrate that α-amanitin-conjugated trastuzumab (T-Ama) potentiated the HER2-targeted therapy and exhibited superior efficacy in treating HER2-low breast cancer with 17p loss. Moreover, treatment with T-Ama induced immunogenic cell death in breast cancer cells and, thereby, delivered greater efficacy in combination with immune checkpoint blockade therapy in preclinical HER2-low breast cancer models. Collectively, 17p loss not only drives breast tumorigenesis but also confers therapeutic vulnerabilities that may be used to develop targeted precision immunotherapy.
Author Info: (1) Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (2) Department of Medical and Molecular Genetics, Indiana Univ
Author Info: (1) Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (2) Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (3) Heidelberg Pharma Research GmbH, Ladenburg 68526, Germany. (4) Heidelberg Pharma Research GmbH, Ladenburg 68526, Germany. (5) Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (6) Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (7) Departments of Surgery and Urology, Immunobiology and Transplant Science Center, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA. Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA. (8) Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (9) Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (10) Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (11) Heidelberg Pharma Research GmbH, Ladenburg 68526, Germany. (12) Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. xz48@iu.edu xiolu@iu.edu. Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. (13) Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. xz48@iu.edu xiolu@iu.edu. Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Indiana University Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
