Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
Zhi L. Teo, Mark J. O’Connor, Stephanie Versaci, Kylie Clarke, Emmaline Brown, Luke W. Percy, Keilly Kuykhoven, Christopher Mintoff, Peter Savas, Balaji Virassamy, Stephen J. Luen, Ann Byrne, Sneha Sant, Geoffrey J. Lindeman, Phillip K. Darcy, Sherene Loi
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.