Evidence map›Paper›PMID 36650183›Full record

ArticleNature communications2023

CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer.

Takuya Tsujino, Tomoaki Takai, Kunihiko Hinohara, Fu Gui, Takeshi Tsutsumi, Xiao Bai, Chenkui Miao, Chao Feng, Bin Gui, Zsofia Sztupinszki and 11 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
86citing papers in PubMed, 4 pooled it
26.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

86 citing papers in PubMed, 4 syntheses or guidelines pooled it, 113 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. A Phase II Trial of Olaparib plus Pembrolizumab in Patients with Recurrent Copy Number-High/p53-Abnormal Endometrial Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
    Trial
  6. A Phase II Trial of Niraparib in Patients with Advanced Pancreatic Cancer Harboring Pathogenic Variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
    Trial
  7. Review
  8. Review
  9. Article
  10. Review
  11. Article
  12. Article
  13. Article
  14. Article
  15. Article
  16. Article
  17. Review
  18. Article
  19. Article
  20. Review

26 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

21 authors at 6 institutions in 4 countries.

Takuya Tsujino *Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
Tomoaki Takai *Division of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
Kunihiko Hinohara *Department of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA, USA.
Fu GuiDivision of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-8329-7118
Takeshi TsutsumiDivision of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-6144-9464
Xiao BaiDivision of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
Chenkui MiaoDivision of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
Chao FengDivision of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
Bin GuiDivision of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
Zsofia SztupinszkiComputational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.
Antoine SimoneauDepartment of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.
Ning XieVancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
Ladan FazliVancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
Xuesen DongVancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.ORCID 0000-0002-3115-3371
Haruhito AzumaDepartment of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan.
Atish D ChoudhuryDepartment of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-9344-6631
Kent W MouwDepartment of Radiation Oncology, Dana-Farber Cancer Institute & Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
Zoltan SzallasiComputational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.ORCID 0000-0001-5395-7509
Lee ZouDepartment of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.ORCID 0000-0003-3094-1058
Adam S KibelDivision of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA.
Li JiaDivision of Urology, Department of Surgery, Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA. ljia@bwh.harvard.edu.ORCID 0000-0003-4017-1157
Brigham and Women's Hospital · USHarvard University · USBoston Children's Hospital · USVancouver General Hospital · CAOsaka University of Pharmaceutical Sciences · JPUniversity of British Columbia · CA

Funding

CHEK2 loss promotes prostate cancer resistance to PARP inhibitorsR21CA267496 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI JIA, LI · 2022 to 2023
$456k
NCI NIH HHS R21 CA267496
6 · The paper itself

Abstract

Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer.

Indexed as

Antineoplastic AgentsProstatic NeoplasmsBRCA1 ProteinDNA RepairDrug Resistance, NeoplasmGenes, BRCA2HumansMalePoly(ADP-ribose) Polymerase InhibitorsAntineoplastic AgentsBRCA1 ProteinPoly(ADP-ribose) Polymerase Inhibitors

Identifiers

PMID36650183
PMCPMC9845315
OpenAlexW4316804884

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.