Evidence map›Paper›PMID 38886371›Full record

ArticleScientific reports2024

In vitro evolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells.

Juan Carlos Jado, Michelle Dow, Krypton Carolino, Adam Klie, Gregory J Fonseca, Trey Ideker, Hannah Carter, Elizabeth A Winzeler

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. 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

8 authors.

Juan Carlos Jado *Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California, San Diego, Gilman Dr., La Jolla, CA, 92093, USA.
Michelle Dow *Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA, 92093, USA.
Krypton CarolinoDivision of Biological Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
Adam KlieDepartment of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA, 92093, USA.
Gregory J FonsecaDepartment of Medicine, Meakins-Christie Laboratories, McGill University Health Centre, 1001 Decaire Blvd, Montreal, QC, H4A 3J1, Canada.
Trey IdekerDepartment of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA, 92093, USA. tideker@ucsd.edu.
Hannah CarterDepartment of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA, 92093, USA. hcarter@ucsd.edu.
Elizabeth A WinzelerDivision of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California, San Diego, Gilman Dr., La Jolla, CA, 92093, USA. ewinzeler@ucsd.edu.

Funding

SYNTHETIC SYSTEMSP50GM085764 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HASTY, JEFF M, IDEKER, TREY · 2010 to 2018
$23.3M
San Diego Biomedical Informatics Education & Research (SABER)T15LM011271 · NLM · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SHAMIM NEMATI · 2012 to 2026
$9.7M
NIGMS NIH HHS P50 GM085764NIH HHS GM085764NLM NIH HHS T15 LM011271
6 · The paper itself

Abstract

In vitro evolution and whole genome analysis has proven to be a powerful method for studying the mechanism of action of small molecules in many haploid microbes but has generally not been applied to human cell lines in part because their diploid state complicates the identification of variants that confer drug resistance. To determine if haploid human cells could be used in MOA studies, we evolved resistance to five different anticancer drugs (doxorubicin, gemcitabine, etoposide, topotecan, and paclitaxel) using a near-haploid cell line (HAP1) and then analyzed the genomes of the drug resistant clones, developing a bioinformatic pipeline that involved filtering for high frequency alleles predicted to change protein sequence, or alleles which appeared in the same gene for multiple independent selections with the same compound. Applying the filter to sequences from 28 drug resistant clones identified a set of 21 genes which was strongly enriched for known resistance genes or known drug targets (TOP1, TOP2A, DCK, WDR33, SLCO3A1). In addition, some lines carried structural variants that encompassed additional known resistance genes (ABCB1, WWOX and RRM1). Gene expression knockdown and knockout experiments of 10 validation targets showed a high degree of specificity and accuracy in our calls and demonstrates that the same drug resistance mechanisms found in diverse clinical samples can be evolved, discovered and studied in an isogenic background.

Indexed as

Antineoplastic AgentsDrug Resistance, NeoplasmHaploidyCell LineGenome, HumanHumansWhole Genome SequencingAntineoplastic Agents

Identifiers

PMID38886371
PMCPMC11183241

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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.