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Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models

Author

Listed:
  • Hyoung Kim

    (University of Pennsylvania)

  • Haineng Xu

    (University of Pennsylvania)

  • Erin George

    (University of Pennsylvania)

  • Dorothy Hallberg

    (Johns Hopkins University School of Medicine)

  • Sushil Kumar

    (University of Pennsylvania)

  • Veena Jagannathan

    (University of Pennsylvania)

  • Sergey Medvedev

    (University of Pennsylvania)

  • Yasuto Kinose

    (University of Pennsylvania)

  • Kyle Devins

    (University of Pennsylvania)

  • Priyanka Verma

    (University of Pennsylvania)

  • Kevin Ly

    (University of Pennsylvania)

  • Yifan Wang

    (Fox Chase Cancer Center)

  • Roger A. Greenberg

    (University of Pennsylvania)

  • Lauren Schwartz

    (University of Pennsylvania)

  • Neil Johnson

    (Fox Chase Cancer Center)

  • Robert B. Scharpf

    (Johns Hopkins University School of Medicine)

  • Gordon B. Mills

    (Oregon Health & Science University School of Medicine)

  • Rugang Zhang

    (The Wistar Institute)

  • Victor E. Velculescu

    (Johns Hopkins University School of Medicine)

  • Eric J. Brown

    (University of Pennsylvania)

  • Fiona Simpkins

    (University of Pennsylvania)

Abstract

Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). Sensitivity to PARPi-ATRi in diverse PARPi and platinum-resistant models, including BRCA1/2 reversion and CCNE1-amplified models, correlate with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis. Surprisingly, BRCA reversion mutations and an ability to form RAD51 foci are frequently not observed in models of acquired PARPi-resistance, suggesting the existence of alternative resistance mechanisms. However, regardless of the mechanisms of resistance, complete and durable therapeutic responses to PARPi-ATRi that significantly increase survival are observed in clinically relevant platinum and acquired PARPi-resistant patient-derived xenografts (PDXs) models. These findings indicate that PARPi-ATRi is a highly promising strategy for OVCAs that acquire resistance to PARPi and platinum.

Suggested Citation

  • Hyoung Kim & Haineng Xu & Erin George & Dorothy Hallberg & Sushil Kumar & Veena Jagannathan & Sergey Medvedev & Yasuto Kinose & Kyle Devins & Priyanka Verma & Kevin Ly & Yifan Wang & Roger A. Greenber, 2020. "Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17127-2
    DOI: 10.1038/s41467-020-17127-2
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    Cited by:

    1. Zixiang Wang & Shourong Wang & Junchao Qin & Xiyu Zhang & Gang Lu & Hongbin Liu & Haiyang Guo & Ligang Wu & Victoria O. Shender & Changshun Shao & Beihua Kong & Zhaojian Liu, 2022. "Splicing factor BUD31 promotes ovarian cancer progression through sustaining the expression of anti-apoptotic BCL2L12," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Jun Dai & Shuyu Zheng & Matías M. Falco & Jie Bao & Johanna Eriksson & Sanna Pikkusaari & Sofia Forstén & Jing Jiang & Wenyu Wang & Luping Gao & Fernando Perez-Villatoro & Olli Dufva & Khalid Saeed & , 2024. "Tracing back primed resistance in cancer via sister cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Taichi Igarashi & Marianne Mazevet & Takaaki Yasuhara & Kimiyoshi Yano & Akifumi Mochizuki & Makoto Nishino & Tatsuya Yoshida & Yukihiro Yoshida & Nobuhiko Takamatsu & Akihide Yoshimi & Kouya Shiraish, 2023. "An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Elena Giudice & Tzu-Ting Huang & Jayakumar R. Nair & Grant Zurcher & Ann McCoy & Darryl Nousome & Marc R. Radke & Elizabeth M. Swisher & Stanley Lipkowitz & Kristen Ibanez & Duncan Donohue & Tyler Mal, 2024. "The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Takuya Tsujino & Tomoaki Takai & Kunihiko Hinohara & Fu Gui & Takeshi Tsutsumi & Xiao Bai & Chenkui Miao & Chao Feng & Bin Gui & Zsofia Sztupinszki & Antoine Simoneau & Ning Xie & Ladan Fazli & Xuesen, 2023. "CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Wei Liu & Hongchao Cao & Jing Wang & Areeg Elmusrati & Bing Han & Wei Chen & Ping Zhou & Xiyao Li & Stephen Keysar & Antonio Jimeno & Cun-Yu Wang, 2024. "Histone-methyltransferase KMT2D deficiency impairs the Fanconi anemia/BRCA pathway upon glycolytic inhibition in squamous cell carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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