Evidence map›Paper›PMID 41898529›Full record

ArticleInternational journal of molecular sciences2026

Genome-Wide CRISPR Screens Identify ABCG2-Mediated Drug Resistance to the Threonine Tyrosine Kinase (TTK) Inhibitor CFI-402257 in Breast Cancer.

Kelsie L Thu, Soode Jafari, Jennifer Silvester, Jennifer Cruickshank, Isabel Soria-Bretones, Kelsey Hodgson, Chantal Tobin, Jillian Haight, Asa P Y Lau, Tessa Bray and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in International journal of molecular sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

14 authors.

Kelsie L ThuKeenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON M5B 1X3, Canada.ORCID 0000-0001-9262-7238
Soode JafariPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Jennifer SilvesterPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Jennifer CruickshankPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Isabel Soria-BretonesPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Kelsey HodgsonPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Chantal TobinPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Jillian HaightPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Asa P Y LauKeenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON M5B 1X3, Canada.ORCID 0009-0009-7423-6028
Tessa BrayPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Drew WakehamPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Mark R BrayPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.
Tak W MakPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.ORCID 0000-0001-6766-861X
David W CesconPrincess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, Canada.ORCID 0000-0002-1080-0998

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

CRISPR screens are a powerful functional genomics approach for identifying genes that confer sensitivity and resistance to anti-cancer therapies. CFI-402257 (luvixasertib, 2257) is a small molecule inhibitor of threonine tyrosine kinase (TTK), a promising therapeutic target in genomically unstable cancers due to its critical role in establishing the spindle assembly checkpoint (SAC) during mitosis. To inform its ongoing development and evaluation in clinical trials, we sought to use CRISPR activation (i.e., gain of function) screens to identify cellular mechanisms of resistance to 2257 in models of triple-negative breast cancer (TNBC). In vitro screens conducted in two TNBC cell lines nominated ABCG2 as the top resistance-conferring gene in both models. Validation studies assessing clonogenic survival and apoptosis confirmed that ABCG2 overexpression enhanced TNBC resistance to 2257 in vitro, while knockdown enhanced sensitivity. These findings suggest that 2257 is a substrate of ABCG2's drug efflux activity. However, overexpression of ABCG2 failed to confer resistance to 2257 in TNBC xenografts grown in mice and treated with a moderately active dose and schedule. Our results highlight the potential impact of drug transporters in in vitro CRISPR screens and the importance of confirming the relevance of drug response mechanisms identified in cultured cells using in vivo models that recapitulate drug pharmacokinetics and pharmacodynamics.

Indexed as

ATP Binding Cassette Transporter, Subfamily G, Member 2Clustered Regularly Interspaced Short Palindromic RepeatsDrug Resistance, NeoplasmNeoplasm ProteinsProtein Kinase InhibitorsProtein Serine-Threonine KinasesTriple Negative Breast NeoplasmsAnimalsAntineoplastic AgentsApoptosisCell Line, TumorDiketopiperazinesFemaleHeterocyclic Compounds, 4 or More RingsHumansMice3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl esterABCG2 protein, humanAntineoplastic AgentsATP Binding Cassette Transporter, Subfamily G, Member 2DiketopiperazinesHeterocyclic Compounds, 4 or More RingsNeoplasm ProteinsProtein Kinase InhibitorsProtein Serine-Threonine KinasesABCG2breast cancerCFI-402257CRISPR screendrug resistanceluvixasertib

Identifiers

PMID41898529
PMCPMC13026355

What Socratic 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 Socratic graph.