Evidence map›Paper›PMID 38454120›Full record

ArticleLeukemia2024

The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma.

Hildo C Lantermans, Fangxue Ma, Annemieke Kuil, Sanne van Kesteren, Sevtap Yasinoglu, Guang Yang, Sara J Buhrlage, Jinhua Wang, Nathanael S Gray, Marie José Kersten and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Leukemia, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing 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

3 citing papers in PubMed.

  1. 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

13 authors.

Hildo C LantermansDepartment of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Fangxue MaDepartment of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Annemieke KuilDepartment of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Sanne van KesterenDepartment of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Sevtap YasinogluDepartment of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Guang YangBing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID 0000-0003-3049-4200
Sara J BuhrlageDepartment of Cancer Biology, Dana-Farber Cancer Institute, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.ORCID 0000-0003-4562-1823
Jinhua WangDepartment of Cancer Biology, Dana-Farber Cancer Institute, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-1214-4103
Nathanael S GrayDepartment of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, USA.ORCID 0000-0001-5354-7403
Marie José KerstenLymphoma and Myeloma Center Amsterdam - LYMMCARE, Amsterdam, The Netherlands.ORCID 0000-0002-8904-3802
Steven P TreonBing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID 0000-0001-6393-6154
Steven T PalsDepartment of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Marcel SpaargarenDepartment of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.ORCID 0000-0002-3135-5109

Funding

Trageting the Multiple Myeloma EpigenomeP50CA100707 · NCI · DANA-FARBER CANCER INSTITUTE · PI ANDERSON, KENNETH C., MUNSHI, NIKHIL C. · 2003 to 2023
$45.0M
KWF Kankerbestrijding (Dutch Cancer Society) 7873NCI NIH HHS P50 CA100707
6 · The paper itself

Abstract

Although Bruton's tyrosine kinase (BTK) inhibitors (BTKi) have significantly improved patient prognosis, mantle cell lymphoma (MCL) is still considered incurable due to primary and acquired resistance. We have recently shown that aberrant expression of the Src-family tyrosine kinase hematopoietic cell kinase (HCK) in MCL correlates with poor prognosis, and that genetic HCK perturbation impairs growth and integrin-mediated adhesion of MCL cells. Here, we show that KIN-8194, a dual inhibitor of BTK and HCK with in vivo activity against Myd88-L265P-driven diffuse large B-cell lymphoma and Waldenström Macroglobulinemia, has a potent growth inhibitory effect in MCL cell lines and primary MCL cells, irrespective of their sensitivity to BTKi (ibrutinib and acalabrutinib). In BTKi-resistant cells this is mediated by inhibition of HCK, which results in repression of AKT-S6 signaling. In addition, KIN-8194 inhibits integrin-mediated adhesion of BTKi-sensitive and insensitive MCL cells to fibronectin and stromal cells in an HCK-dependent manner. Finally, we show that MCL cells with acquired BTKi resistance retain their sensitivity to KIN-8194. Taken together, our data demonstrate that KIN-8194 inhibits growth and integrin-mediated adhesion of BTKi-sensitive MCL cells, as well as MCL cells with primary or acquired BTKi resistance. This renders KIN-8194 a promising novel treatment for MCL patients.

Indexed as

Agammaglobulinaemia Tyrosine KinaseCell AdhesionCell ProliferationDrug Resistance, NeoplasmIntegrinsLymphoma, Mantle-CellProtein Kinase InhibitorsProto-Oncogene Proteins c-hckAdenineCell Line, TumorHumansPyrimidinesSignal TransductionAdenineAgammaglobulinaemia Tyrosine KinaseBTK protein, humanHCK protein, humanIntegrinsProtein Kinase InhibitorsProto-Oncogene Proteins c-hckPyrimidines

Identifiers

PMID38454120
PMCPMC11216997

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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.