Evidence map›Paper›PMID 32562246›Full record

ArticleJournal of neuro-oncology2020

PARP inhibition suppresses the emergence of temozolomide resistance in a model system.

Alice L Yuan, Mathieu Meode, Melanie Tan, Lori Maxwell, Elizabeth A Bering, Haley Pedersen, Jacob Willms, Jenny Liao, Sophie Black, J Gregory Cairncross and 1 more

Abstract read
PubMed Publisher
In one paragraph

Article in Journal of neuro-oncology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
0.8field-weighted citation impact, top 28% 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

6 citing papers in PubMed, 14 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Review
  5. Review
  6. Review
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 at 1 institution in 1 country.

Alice L Yuan *Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada.
Mathieu Meode *Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada.
Melanie TanClark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada.
Lori MaxwellClark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada.
Elizabeth A BeringClark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada.
Haley PedersenClark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada.
Jacob WillmsClark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada.
Jenny LiaoClark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada.
Sophie BlackClark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada.
J Gregory Cairncross *Departments of Clinical Neurosciences, University of Calgary, HRIC 2AA-07, 3280 Hospital Drive NW, Calgary, AB, T2N4, Canada.
Michael D Blough *Departments of Clinical Neurosciences, University of Calgary, HRIC 2AA-07, 3280 Hospital Drive NW, Calgary, AB, T2N4, Canada. mdblough@ucalgary.ca.ORCID http://orcid.org/0000-0002-1151-3552
University of Calgary · CA

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

introductionTemozolomide (TMZ) is a life prolonging DNA alkylating agent active against glioblastomas (GBM) in which the O6-methylguanine-DNA methyltransferase (MGMT) gene is silenced by promoter methylation. Unfortunately acquired TMZ resistance severely undermines its clinical efficacy. Using an in vitro model, we tested whether poly (ADP-ribose) polymerase-1 and -2 (PARP) inhibition could suppress the emergence of resistance to enhance the effectiveness of TMZ.

methodsUsing the MGMT-methylated GBM line U251N, in which TMZ resistance can be induced, we developed a method to rapidly recreate mechanisms of TMZ resistance seen in GBMs, including MMR mutations and MGMT re-expression. We then assessed whether TMZ resistant U251N sub-clones could be re-sensitized to TMZ by co-treatment with the PARP inhibitor ABT-888, and also whether the emergence of resistance could be suppressed by PARP inhibition.

resultsU251N cultures chronically exposed to TMZ developed discrete colonies that expanded during TMZ treatment. These colonies were isolated, expanded further as sub-clones, and assessed for mechanisms of TMZ resistance. Most resistant sub-clones had detectable mutations in one or more mismatch repair (MMR) genes, frequently MSH6, and displayed infrequent re-expression of MGMT. TMZ resistance was associated with isolated poly(ADP-ribose) (pADPr) up-regulation in one sub-clone and was unexplained in several others. TMZ resistant sub-clones regressed during co-treatment with TMZ and ABT-888, and early co-treatment of U251N parental cultures suppressed the emergence of TMZ resistant colonies.

conclusionIn a model of acquired resistance, co-treatment with TMZ and a PARP inhibitor had two important benefits: re-sensitization of TMZ resistant cells and suppression of TMZ resistance.

Indexed as

Antineoplastic Agents, AlkylatingApoptosisCell ProliferationDrug Resistance, NeoplasmGene Expression Regulation, NeoplasticGlioblastomaHumansPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsTemozolomideTumor Cells, CulturedAntineoplastic Agents, AlkylatingPARP1 protein, humanPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsTemozolomideABT-888GBMGlioblastomaMGMTPARPTemozolomide

Identifiers

PMID32562246
OpenAlexW3036245422

What OpenQuestion holds

Textmetadata
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.