联合抑制PARP和WEE1在BRCA1/2野生型三阴性乳腺癌中引发抗肿瘤免疫应答。
Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer.
发表日期：2023 Aug 15
作者：
Zhi Ling Teo, Mark J O'Connor, Stephanie Versaci, Kylie A Clarke, Emmaline R Brown, Luke W Percy, Keilly Kuykhoven, Christopher P Mintoff, Peter Savas, Balaji Virassamy, Stephen J Luen, Ann Byrne, Sneha Sant, Geoffrey J Lindeman, Phillip K Darcy, Sherene Loi
来源：
npj Breast Cancer
摘要：
在三阴性乳腺癌（TNBC）的治疗中需要与免疫疗法有效结合的新型治疗策略。我们证明，联合PARP和WEE1抑制在BRCA1/2野生型TNBC的临床前模型中具有协同作用，能够有效控制肿瘤生长。PARP抑制剂（PARPi）奥拉帕尼布与WEE1抑制剂（WEE1i）阿达沃塞替布的联合治疗触发了抗肿瘤免疫反应的增强，包括STING通路的激活。与STING激动剂的联合应用进一步改善了肿瘤的持久性回归，并在BRCA1/2野生型TNBC小鼠肿瘤模型中显著提高了生存结果。此外，我们已经确定基线肿瘤浸润淋巴细胞（TIL）水平作为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。© 2023. Springer Nature Limited.
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.© 2023. Springer Nature Limited.