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

被引：0
|
作者：
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
机构：
[1] Peter MacCallum Cancer Centre,Sir Peter MacCallum Department of Oncology
[2] The University of Melbourne,Cancer Biology and Stem Cells Division
[3] AstraZeneca Oncology,Department of Medicine
[4] The Walter and Eliza Hall Institute of Medical Research,Cancer Immunology Research
[5] University of Melbourne,undefined
[6] Peter MacCallum Cancer Centre,undefined
来源：
npj Breast Cancer | / 9卷
关键词：
D O I：
暂无
中图分类号：
学科分类号：
摘要：
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.
引用
收藏
相关论文
共 50 条
  • [21] The BRCA1 promoter methylation is one of the mechanisms of th BRCA1 dysfunction of triple-negative breast cancer
    Yamashita, N.
    Tokunaga, E.
    Tanaka, K.
    Saeki, H.
    Oki, E.
    Kitao, H.
    Morita, M.
    Maehara, Y.
    CANCER RESEARCH, 2013, 73
  • [22] Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer
    Wong-Brown, Michelle W.
    Meldrum, Cliff J.
    Carpenter, Jane E.
    Clarke, Christine L.
    Narod, Steven A.
    Jakubowska, Anna
    Rudnicka, Helena
    Lubinski, Jan
    Scott, Rodney J.
    BREAST CANCER RESEARCH AND TREATMENT, 2015, 150 (01) : 71 - 80
  • [23] Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer
    Michelle W. Wong-Brown
    Cliff J. Meldrum
    Jane E. Carpenter
    Christine L. Clarke
    Steven A. Narod
    Anna Jakubowska
    Helena Rudnicka
    Jan Lubinski
    Rodney J. Scott
    Breast Cancer Research and Treatment, 2015, 150 : 71 - 80
  • [24] Letter to the Editor in response to paper BRCA1 promoter methylation in triple-negative breast cancer……
    Lonning, Per Eystein
    Nikolaienko, Oleksii
    Knappskog, Stian
    BREAST CANCER RESEARCH AND TREATMENT, 2025, 210 (01) : 227 - 228
  • [25] Germline and tumor BRCA1/2 pathogenic variants in Chinese triple-negative breast carcinomas
    Gang Ji
    Longlong Bao
    Qianlan Yao
    Jing Zhang
    Xiaoli Zhu
    Qianming Bai
    Zhiming Shao
    Wentao Yang
    Xiaoyan Zhou
    Journal of Cancer Research and Clinical Oncology, 2021, 147 : 2935 - 2944
  • [26] Germline and tumor BRCA1/2 pathogenic variants in Chinese triple-negative breast carcinomas
    Ji, Gang
    Bao, Longlong
    Yao, Qianlan
    Zhang, Jing
    Zhu, Xiaoli
    Bai, Qianming
    Shao, Zhiming
    Yang, Wentao
    Zhou, Xiaoyan
    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, 2021, 147 (10) : 2935 - 2944
  • [27] PARP1, BRCA1 and androgen receptor expression in triple-negative breast cancer patients treated with neoadjuvant chemotherapy
    Rashed, Hayam E.
    Monged, Randa E.
    Nawar, Nashwa
    Alattar, Ahmed Z.
    Alnagar, Ahmed A.
    Abdelhamid, Mohamed I.
    Abdelaziz, Osama
    Said, Nelly M.
    REVISTA DE SENOLOGIA Y PATOLOGIA MAMARIA, 2022, 35 (04): : 228 - 235
  • [28] BRCA1 methylation contributes to the triple-negative breast cancer phenotype.
    Nwachukwu, C.
    Grushko, T. A.
    Xu, J.
    Khramtsov, A.
    Olopade, O., I
    CANCER RESEARCH, 2009, 69 (02) : 266S - 266S
  • [29] Targeting Replicative Stress and DNA Repair by Combining PARP and Wee1 Kinase Inhibitors Is Synergistic in Triple Negative Breast Cancers with Cyclin E or BRCA1 Alteration
    Chen, Xian
    Yang, Dong
    Carey, Jason P. W.
    Karakas, Cansu
    Albarracin, Constance
    Sahin, Aysegul A.
    Arun, Banu K.
    Guray Durak, Merih
    Li, Mi
    Kohansal, Mehrnoosh
    Bui, Tuyen N.
    Ha, Min-Jin
    Hunt, Kelly K.
    Keyomarsi, Khandan
    CANCERS, 2021, 13 (07)
  • [30] Transcriptoma analyses in triple-negative breast cancer with BRCA1 germline mutation
    Nakamura, Kivvi Duarte
    Ferreira, Elisa
    Ramalho, Rodrigo
    Brianese, Rafael
    Carraro, Dirce
    CANCER RESEARCH, 2017, 77
12345