Research ArticleCancer

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

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Science Translational Medicine  10 Feb 2021:
Vol. 13, Issue 580, eabc6894
DOI: 10.1126/scitranslmed.abc6894

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An “Ama”-zing antibody-drug conjugate

Antibody-drug conjugates (ADCs) targeting HER2 are an attractive candidate for treating patients with HER2+ breast cancer. Here, Li et al. developed an ADC that is especially effective at killing breast cancer cells that express HER2 at low levels. HER2-low breast cancer cells often have loss of chromosome 17p, which the authors showed sensitizes tumor cells to the drug α-amanitin. When the authors treated mice bearing HER2-low tumors with an ADC of trastuzumab and α-amanitin, T-Ama, they found that T-Ama induced immunogenic cell death of tumor cells, which enhanced the response to immune checkpoint blockade. Thus, T-Ama may represent an effective treatment strategy for patients with HER2-low breast cancer.

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.

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