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

ZL Teo; MJ O’Connor; S Versaci; KA Clarke; ER Brown; LW Percy; K Kuykhoven; CP Mintoff; P Savas; B Virassamy; SJ Luen; A Byrne; S Sant; GJ Lindeman; PK Darcy; S Loi

Journal article

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

ZL Teo, MJ O’Connor, S Versaci, KA Clarke, ER Brown, LW Percy, K Kuykhoven, CP Mintoff, P Savas, B Virassamy, SJ Luen, A Byrne, S Sant, GJ Lindeman, PK Darcy, S Loi

Npj Breast Cancer | Published : 2023

DOI: 10.1038/s41523-023-00568-5

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 baselin..

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University of Melbourne Researchers

Zhi Ling Teo Author

Peter Savas Author

Balaji Virassamy Author

Stephen Luen Author

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Grants

Awarded by Breast Cancer Research Foundation

Funding Acknowledgements

The authors wish to acknowledge staff from the Peter MacCallum Cancer Centre Animal Facility, Flow Cytometry Facility, Centre for Advanced Histology and Microscopy, and Molecular Genomics Core Facility for their assistance. Z.L.T. was supported by a NHMRC Early Career Fellowship (1106967). G.J.L. was supported by a NHMRC Senior Principal Research Fellowship (1078730) and Leadership Fellowship (1175960). P.K.D. was supported by a NHMRC Senior Research Fellowship (1136680). S.L. is supported by a National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York.