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

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

doi:10.1038/s41523-023-00568-5

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

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

Authors

Zhi Ling Teo^{1

2}, Mark J O'Connor³, Stephanie Versaci¹, Kylie A Clarke¹, Emmaline R Brown¹, Luke W Percy¹, Keilly Kuykhoven¹, Christopher P Mintoff¹, Peter Savas^{1

2}, Balaji Virassamy¹, Stephen J Luen^{1

2}, Ann Byrne¹, Sneha Sant¹, Geoffrey J Lindeman^{4

5}, Phillip K Darcy^{1

2

6}, Sherene Loi^{7

8}

Affiliations

¹ Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
² Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia.
³ AstraZeneca Oncology, Cambridge, UK.
⁴ Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
⁵ Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
⁶ Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁷ Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia. sherene.loi@petermac.org.
⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, 3010, Australia. sherene.loi@petermac.org.

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.