npj Breast Cancer (Aug 2023)

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
https://doi.org/10.1038/s41523-023-00568-5
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 16

Abstract

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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.