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

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 PAR...

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Detalles Bibliográficos
Autores principales: Teo, Zhi Ling, O’Connor, Mark J., Versaci, Stephanie, Clarke, Kylie A., Brown, Emmaline R., Percy, Luke W., Kuykhoven, Keilly, Mintoff, Christopher P., Savas, Peter, Virassamy, Balaji, Luen, Stephen J., Byrne, Ann, Sant, Sneha, Lindeman, Geoffrey J., Darcy, Phillip K., Loi, Sherene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427618/
https://www.ncbi.nlm.nih.gov/pubmed/37582853
http://dx.doi.org/10.1038/s41523-023-00568-5
Descripción
Sumario: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.

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