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

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Τίτλος: Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
Συγγραφείς: Teo, ZL, O’Connor, MJ, Versaci, S, Clarke, KA, Brown, ER, Percy, LW, Kuykhoven, K, Mintoff, CP, Savas, P, Virassamy, B, Luen, SJ, Byrne, A, Sant, S, Lindeman, GJ, Darcy, PK, Loi, S
Στοιχεία εκδότη: NATURE PORTFOLIO
Έτος έκδοσης: 2023
Συλλογή: The University of Melbourne: Digital Repository
Περιγραφή: 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.
Τύπος εγγράφου: article in journal/newspaper
Γλώσσα: English
ISSN: 2374-4677
Relation: NHMRC/1106967; NHMRC/1136680; https://hdl.handle.net/11343/338785
Διαθεσιμότητα: https://hdl.handle.net/11343/338785
Rights: https://creativecommons.org/licenses/by/4.0 ; CC BY
Αριθμός Καταχώρησης: edsbas.9AD4EED1
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  – Url: https://hdl.handle.net/11343/338785#
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  Data: Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
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  Data: 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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