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

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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
机构：
[1] Peter MacCallum Cancer Centre,Sir Peter MacCallum Department of Oncology
[2] The University of Melbourne,Cancer Biology and Stem Cells Division
[3] AstraZeneca Oncology,Department of Medicine
[4] The Walter and Eliza Hall Institute of Medical Research,Cancer Immunology Research
[5] University of Melbourne,undefined
[6] Peter MacCallum Cancer Centre,undefined
来源：
npj Breast Cancer | / 9卷
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摘要：
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.
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