Evidence map›Paper›PMID 29180466›Full record

ArticleCancer research2018

Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer.

Jason P W Carey, Cansu Karakas, Tuyen Bui, Xian Chen, Smruthi Vijayaraghavan, Yang Zhao, Jing Wang, Keith Mikule, Jennifer K Litton, Kelly K Hunt and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.

0numbers the graph read from it
0cells of the map it votes in
81citing 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

81 citing papers in PubMed.

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

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

11 authors.

Jason P W CareyDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. kkeyomar@mdanderson.org jpcarey@mdanderson.org.
Cansu KarakasDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Tuyen BuiDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Xian ChenDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Smruthi VijayaraghavanDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Yang ZhaoDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jing WangDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Keith MikuleTesaro Biopharmaceuticals, Waltham, Massacheusetts.
Jennifer K LittonDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Kelly K HuntDepartment of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Khandan KeyomarsiDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. kkeyomar@mdanderson.org jpcarey@mdanderson.org.

Funding

Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8M
Proteolytic Processing of Cyclin E in Breast CancerR01CA087548 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KEYOMARSI, KHANDAN · 2001 to 2015
$4.1M
Targeting the cell cycle in triple negative breast cancerR01CA152228 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KEYOMARSI, KHANDAN · 2011 to 2015
$2.3M
NCI NIH HHS P30 CA016672NCI NIH HHS R01 CA087548NCI NIH HHS R01 CA152228
6 · The paper itself

Abstract

PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial-mesenchymal transition and cancer stem-like cell phenotypes. Notably, dinaciclib resensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon, and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.

Indexed as

Synthetic Lethal MutationsAnimalsApoptosisBRCA1 ProteinBRCA2 ProteinBridged Bicyclo Compounds, HeterocyclicCell ProliferationCyclic N-OxidesDNA DamageDNA RepairDrug Resistance, NeoplasmDrug Therapy, CombinationFemaleHumansIndolizinesMiceBRCA1 ProteinBRCA1 protein, humanBRCA2 ProteinBRCA2 protein, humanBridged Bicyclo Compounds, HeterocyclicCyclic N-OxidesdinaciclibIndolizinesMYC protein, humanPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsProto-Oncogene Proteins c-mycPyridinium Compounds

Identifiers

PMID29180466
PMCPMC5811386

What OpenQuestion holds

Textmetadata
LicenceTDM
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.