Combined PARP and WEE1 Inhibition Triggers Anti-tumor Immune Response in BRCA1/2 Wildtype Triple-negative Breast Cancer

Overview

Journal NPJ Breast Cancer

Date 2023 Aug 15

PMID 37582853

Authors

Zhi Ling Teo

Mark J OConnor

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

Affiliations

Soon will be listed here.

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.

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