Evidence map›Paper›PMID 39375715›Full record

ArticleMolecular cancer2024

Proapoptotic activity of JNK-sensitive BH3-only proteins underpins ovarian cancer response to replication checkpoint inhibitors.

Annapoorna Venkatachalam, Cristina Correia, Kevin L Peterson, Xianon Hou, Paula A Schneider, Annabella R Strathman, Karen S Flatten, Chance C Sine, Emily A Balczewski, Cordelia D McGehee and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
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

4 citing papers in PubMed.

  1. BCLXSignal transduction and targeted therapy · 2026
    Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors.

Annapoorna VenkatachalamDepartment of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Cristina CorreiaDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Kevin L PetersonDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Xianon HouDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Paula A SchneiderDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Annabella R StrathmanDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Karen S FlattenDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Chance C SineDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Emily A BalczewskiDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Cordelia D McGeheeDepartment of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Melissa C LarsonDivision of Clinical Trials and Biostatistics, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Laura N DuffieldDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
X Wei MengDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Nicole D VinceletteDepartment of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Husheng DingDepartment of Oncology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Ann L ObergDivision of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Fergus J CouchDivision of Experimental Pathology, Department of Laboratory Medicine, and Pathology, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Elizabeth M SwisherDepartment of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
Hu LiDepartment of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
S John WerohaDepartment of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA.
Scott H KaufmannDepartment of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, 200 First Street, S.W., Rochester, MN, 55905, USA. Kaufmann.Scott@Mayo.edu.

Funding

Women's Cancer ProgramP30CA015083 · NCI · MAYO CLINIC ROCHESTER · PI Lila J. Rutten · 1985 to 2026
$151.3M
Use of microfluidic tumor cultures to enable clinical trials of therapies for ovarian cancerP50CA136393 · NCI · MAYO CLINIC ROCHESTER · PI SCOTT H KAUFMANN · 2009 to 2026
$37.0M
Medical Scientist Traning Program at Mayo ClinicT32GM065841 · NIGMS · MAYO CLINIC ROCHESTER · PI KAUFMANN, SCOTT H, SCHIMMENTI, LISA A · 2003 to 2022
$5.8M
The contribution of RAD51C and RAD51D to breast and ovarian cancerR01CA225662 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH, WEROHA, SARAVUT · 2018 to 2024
$2.5M
A Systems Biology Approach to Mechanisms of PARP Inhibitor Resistance in Ovarian CancerF30CA213737 · NCI · MAYO CLINIC ROCHESTER · PI MCGEHEE, CORDELIA · 2017 to 2021
$190k
NCI NIH HHS F30 CA213737NCI NIH HHS P30 CA015083NCI NIH HHS P50 CA136393NCI NIH HHS R01 CA225662NIGMS NIH HHS T32 GM065841
6 · The paper itself

Abstract

Recent studies indicate that replication checkpoint modulators (RCMs) such as inhibitors of CHK1, ATR, and WEE1 have promising monotherapy activity in solid tumors, including platinum-resistant high grade serous ovarian cancer (HGSOC). However, clinical response rates are generally below 30%. While RCM-induced DNA damage has been extensively examined in preclinical and clinical studies, the link between replication checkpoint interruption and tumor shrinkage remains incompletely understood. Here we utilized HGSOC cell lines and patient-derived xenografts (PDXs) to study events leading from RCM treatment to ovarian cancer cell death. These studies show that RCMs increase CDC25A levels and CDK2 signaling in vitro, leading to dysregulated cell cycle progression and increased replication stress in HGSOC cell lines independent of homologous recombination status. These events lead to sequential activation of JNK and multiple BH3-only proteins, including BCL2L11/BIM, BBC3/PUMA and the BMF, all of which are required to fully initiate RCM-induced apoptosis. Activation of the same signaling pathway occurs in HGSOC PDXs that are resistant to poly(ADP-ribose) polymerase inhibitors but respond to RCMs ex vivo with a decrease in cell number in 3-dimensional culture and in vivo with xenograft shrinkage or a significantly diminished growth rate. These findings identify key cell death-initiating events that link replication checkpoint inhibition to antitumor response in ovarian cancer.

Indexed as

ApoptosisOvarian NeoplasmsXenograft Model Antitumor AssaysAnimalsApoptosis Regulatory ProteinsCell Line, TumorDNA ReplicationFemaleHumansMiceSignal TransductionApoptosis Regulatory ProteinsApoptosisATR inhibitorBH3 proteinsCHK1 inhibitorHigh grade serous ovarian cancerReplication stressWEE1 inhibitor

Identifiers

PMID39375715
PMCPMC11457406

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Registered trials

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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.