Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
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2023-12-01
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npj Breast Cancer
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NATURE PORTFOLIO
Melbourne Authors
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Sir Peter MacCallum Department of Oncology
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Medicine (RMH)
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Journal Article
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Teo, Z. L., O’Connor, M. J., Versaci, S., Clarke, K. A., Brown, E. R., Percy, L. W., Kuykhoven, K., Mintoff, C. P., Savas, P., Virassamy, B., Luen, S. J., Byrne, A., Sant, S., Lindeman, G. J., Darcy, P. K. & Loi, S. (2023). Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer. Npj Breast Cancer, 9 (1), https://doi.org/10.1038/s41523-023-00568-5.
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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.