Evidence map›Paper›PMID 39395205›Full record

ArticleMolecular oncology2025

Targeting rapid TKI-induced AXL upregulation overcomes adaptive ERK reactivation and exerts antileukemic effects in FLT3/ITD acute myeloid leukemia.

Tessa S Seale, Li Li, J Kyle Bruner, Melody Chou, Bao Nguyen, Jaesung Seo, Ruiqi Zhu, Mark J Levis, Christine A Pratilas, Donald Small

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular oncology, 2025. 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
–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

6 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
  4. [Role of Receptor Tyrosine Kinase AXL in Cancer Targeted Therapy Drug Resistance].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2026
    Review
  5. Article
  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

10 authors.

Tessa S SealeDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Li LiDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Kyle BrunerDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Melody ChouDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bao NguyenDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jaesung SeoDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ruiqi ZhuDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Mark J LevisDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Christine A PratilasDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Donald SmallDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID https://orcid.org/0009-0006-3410-7000

Funding

Translational Research Central ServicesP30CA006973 · NCI · JOHNS HOPKINS UNIVERSITY · PI ALAN KEITH MEEKER · 1985 to 2026
$208.6M
Giant Food Pediatric Cancer FundNCI NIH HHS P30 CA006973
6 · The paper itself

Abstract

Acute myeloid leukemia (AML) patients with the FMS-related receptor tyrosine kinase 3 internal tandem duplication (FLT3/ITD) mutation have a poorer prognosis, and treatment with FLT3 tyrosine kinase inhibitors (TKIs) has been hindered by resistance mechanisms. One such mechanism is known as adaptive resistance, in which downstream signaling pathways are reactivated after initial inhibition. Past work has shown that FLT3/ITD cells undergo adaptive resistance through the reactivation of extracellular signal-regulated kinase (ERK) signaling within 24 h of sustained FLT3 inhibition. We investigated the mechanism(s) responsible for this ERK reactivation and hypothesized that targeting tyrosine-protein kinase receptor UFO (AXL), another receptor tyrosine kinase that has been implicated in cancer resistance, may overcome the adaptive ERK reactivation. Experiments revealed that AXL is upregulated and activated in FLT3/ITD cell lines mere hours after commencing TKI treatment. AXL inhibition combined with FLT3 inhibition to decrease the ERK signal rebound and to exert greater anti-leukemia effects than with either treatment alone. Finally, we observed that TKI-induced AXL upregulation occurs in patient samples, and combined inhibition of both AXL and FLT3 increased efficacy in our in vivo models. Taken together, these data suggest that AXL plays a role in adaptive resistance in FLT3/ITD AML and that combined AXL and FLT3 inhibition might improve FLT3/ITD AML patient outcomes.

Indexed as

Extracellular Signal-Regulated MAP Kinasesfms-Like Tyrosine Kinase 3Leukemia, Myeloid, AcuteProtein Kinase InhibitorsProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesUp-RegulationAnimalsAxl Receptor Tyrosine KinaseCell Line, TumorHumansMAP Kinase Signaling SystemMiceTandem Repeat SequencesXenograft Model Antitumor AssaysAXL protein, humanAxl Receptor Tyrosine KinaseExtracellular Signal-Regulated MAP KinasesFLT3 protein, humanfms-Like Tyrosine Kinase 3Protein Kinase InhibitorsProto-Oncogene ProteinsReceptor Protein-Tyrosine Kinasesadaptive responsecancer resistanceFLT3/ITD AMLRTK signalingtargeted therapy

Identifiers

PMID39395205
PMCPMC12077278

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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.