Targeted immunotherapy for HER2-low breast cancer with 17p loss

被引:27
作者
Li, Yujing [1 ]
Sun, Yifan [1 ]
Kulke, Michael [2 ]
Hechler, Torsten [2 ]
Van der Jeught, Kevin [1 ]
Dong, Tianhan [3 ]
He, Bin [4 ,5 ,6 ]
Miller, Kathy D. [7 ,8 ]
Radovich, Milan [7 ,9 ]
Schneider, Bryan P. [7 ,8 ]
Pahl, Andreas [2 ]
Zhang, Xinna [1 ,7 ]
Lu, Xiongbin [1 ,7 ,10 ]
机构
[1] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA
[2] Heidelberg Pharma Res GmbH, D-68526 Ladenburg, Germany
[3] Indiana Univ Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA
[4] Houston Methodist Hosp, Immunobiol & Transplant Sci Ctr, Houston Methodist Canc Ctr, Houston Methodist Res Inst,Dept Surg, Houston, TX 77030 USA
[5] Houston Methodist Hosp, Immunobiol & Transplant Sci Ctr, Houston Methodist Canc Ctr, Houston Methodist Res Inst,Dept Urol, Houston, TX 77030 USA
[6] Cornell Univ, Dept Med, Weill Cornell Med, New York, NY 10065 USA
[7] Indiana Univ Sch Med, Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA
[8] Indiana Univ Sch Med, Dept Med, Div Hematol Oncol, Indianapolis, IN 46202 USA
[9] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN 46202 USA
[10] Indiana Univ Sch Med, Indiana Univ, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA
关键词
IMMUNOGENIC CELL-DEATH; TRASTUZUMAB EMTANSINE; ANTIBODY; DRUG; ACTIVATION; SURVIVAL;
D O I
10.1126/scitranslmed.abc6894
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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, alpha-amanitin. Here, we demonstrate that alpha-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.
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页数:17
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