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PARP与WEE1联合抑制在BRCA1/2野生型三阴性乳腺癌中引发抗肿瘤免疫反应。

Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer.

作者信息

Teo Zhi Ling, O'Connor Mark J, Versaci Stephanie, Clarke Kylie A, Brown Emmaline R, Percy Luke W, Kuykhoven Keilly, Mintoff Christopher P, Savas Peter, Virassamy Balaji, Luen Stephen J, Byrne Ann, Sant Sneha, Lindeman Geoffrey J, Darcy Phillip K, Loi Sherene

机构信息

Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.

Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia.

出版信息

NPJ Breast Cancer. 2023 Aug 15;9(1):68. doi: 10.1038/s41523-023-00568-5.

DOI:10.1038/s41523-023-00568-5
PMID:37582853
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10427618/
Abstract

Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumour growth in BRCA1/2 wild-type TNBC preclinical models. The PARP inhibitor (PARPi) olaparib combined with the WEE1 inhibitor (WEE1i) adavosertib triggered increases in anti-tumour immune responses, including STING pathway activation. Combinations with a STING agonist resulted in further improved durable tumour regression and significant improvements in survival outcomes in murine tumour models of BRCA1/2 wild-type TNBC. In addition, we have identified baseline tumour-infiltrating lymphocyte (TIL) levels as a potential predictive biomarker of response to PARPi, WEE1i and immunotherapies in BRCA1/2 wild-type TNBC.

摘要

三阴性乳腺癌（TNBC）的治疗需要能够与免疫疗法有效结合的新型治疗策略。我们证明，在BRCA1/2野生型TNBC临床前模型中，PARP和WEE1联合抑制在控制肿瘤生长方面具有协同作用。PARP抑制剂（PARPi）奥拉帕利与WEE1抑制剂（WEE1i）阿伐替尼联合使用可引发抗肿瘤免疫反应增加，包括STING通路激活。与STING激动剂联合使用可进一步改善持久的肿瘤消退，并显著改善BRCA1/2野生型TNBC小鼠肿瘤模型的生存结果。此外，我们已确定基线肿瘤浸润淋巴细胞（TIL）水平是BRCA1/2野生型TNBC对PARPi、WEE1i和免疫疗法反应的潜在预测生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82b/10427618/dad668a6d048/41523_2023_568_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82b/10427618/99e977042ccc/41523_2023_568_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82b/10427618/3ae400d8de39/41523_2023_568_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82b/10427618/42aaaee6aa1a/41523_2023_568_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82b/10427618/dad668a6d048/41523_2023_568_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82b/10427618/99e977042ccc/41523_2023_568_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82b/10427618/3ae400d8de39/41523_2023_568_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82b/10427618/42aaaee6aa1a/41523_2023_568_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e82b/10427618/dad668a6d048/41523_2023_568_Fig4_HTML.jpg

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本文引用的文献

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Doxorubicin Conjugation to Reovirus Improves Oncolytic Efficacy in Triple-Negative Breast Cancer.
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