Multi-omics profiling identifies triciribine as a biomarker-guided antimetabolite therapy for acute lymphoblastic leukemia.
9 affiliations
- 1Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Tomtebodavägen 23A, 171 65, Solna, Sweden. [email protected].
- 2Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Tomtebodavägen 23A, 171 65, Solna, Sweden.
- 3Swedish Metabolomics Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.
- 4Molecular Precision Medicine, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Tomtebodavägen 23A, 171 65, Solna, Sweden.
- 5Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Tomtebodavägen 23A, 171 65, Solna, Sweden.
- 6Department of Oncology-Pathology, Karolinska Institutet, J6:140 BioClinicum, Akademiska stråket 1, 171 64, Solna, Sweden.
- 7Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65, Stockholm, Sweden.
- 8Swedish Metabolomics Centre, Department of Plant Physiology, Umeå University, Umeå, Sweden.
- 9Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Tomtebodavägen 23A, 171 65, Solna, Sweden. [email protected].
Abstract
Acute lymphoblastic leukemia (ALL) exhibits molecular and metabolic heterogeneity that limits therapeutic efficacy. Although antimetabolites remain central to ALL treatment, determinants of therapeutic sensitivity and resistance remain incompletely understood. Here, we investigated the activity and molecular response landscape of the purine analog triciribine (TCN) across diverse ALL models using integrated phosphoproteomics, thermal proteome profiling, and quantitative proteomics. TCN showed potent cytotoxicity across ALL cell lines and a drug response profile distinct from canonical PI3K-Akt-mTOR inhibitors. Early phosphoproteomics revealed no consistent suppression of Akt pathway signaling, with transient activation of several Akt-associated readouts and inhibition of cyclin-dependent kinase signaling. The monophosphorylated metabolite TCN-P was the predominant intracellular active species, and adenosine kinase (ADK) was required for TCN-P generation and cytotoxicity. Proteome Integral Solubility Alteration profiling identified candidate TCN-P interactions involving nucleotide metabolism, DNA replication, and protein synthesis, associated with impaired purine biosynthesis, DNA damage, translational stress, and cell-cycle perturbation. Across ALL cell lines and primary samples, ADK levels correlated positively with TCN sensitivity, supporting ADK-dependent metabolism as a major determinant of therapeutic response. Together, these findings identify TCN as a metabolically activated antileukemic agent with broad antimetabolite activity and nominate ADK as a potential predictive biomarker for precision therapy in ALL.
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BibTeX
@article{qi2026multiomics,
title = {{Multi-omics profiling identifies triciribine as a biomarker-guided antimetabolite therapy for acute lymphoblastic leukemia.}},
author = {Xuekang Qi and Georgios Mermelekas and Ondrej Hodek and Luay Aswad and Quentin Glaziou and Isabelle Rose Leo and Nona Struyf and Femke M Hormann and Ioannis Siavelis and Henri Colyn Bwanika and Owen F J Hovey and Martin Haraldsson and Sean G Rudd and Annika I Johansson and Tom Erkers and Katja Pokrovskaja Tamm and Janne Lehtiö and Rozbeh Jafari},
journal = {NPJ precision oncology},
year = {2026},
month = oct,
doi = {10.1038/s41698-026-01736-z},
url = {https://europepmc.org/article/MED/42875447},
note = {CC BY},
}
RIS
TY - JOUR
TI - Multi-omics profiling identifies triciribine as a biomarker-guided antimetabolite therapy for acute lymphoblastic leukemia.
AU - Xuekang Qi
AU - Georgios Mermelekas
AU - Ondrej Hodek
AU - Luay Aswad
AU - Quentin Glaziou
AU - Isabelle Rose Leo
AU - Nona Struyf
AU - Femke M Hormann
AU - Ioannis Siavelis
AU - Henri Colyn Bwanika
AU - Owen F J Hovey
AU - Martin Haraldsson
AU - Sean G Rudd
AU - Annika I Johansson
AU - Tom Erkers
AU - Katja Pokrovskaja Tamm
AU - Janne Lehtiö
AU - Rozbeh Jafari
PY - 2026
DA - 2026/10/14
JO - NPJ precision oncology
DO - 10.1038/s41698-026-01736-z
UR - https://europepmc.org/article/MED/42875447
AB - Acute lymphoblastic leukemia (ALL) exhibits molecular and metabolic heterogeneity that limits therapeutic efficacy. Although antimetabolites remain central to ALL treatment, determinants of therapeutic sensitivity and resistance remain incompletely understood. Here, we investigated the activity and molecular response landscape of the purine analog triciribine (TCN) across diverse ALL models using integrated phosphoproteomics, thermal proteome profiling, and quantitative proteomics. TCN showed potent cytotoxicity across ALL cell lines and a drug response profile distinct from canonical PI3K-Akt-mTOR inhibitors. Early phosphoproteomics revealed no consistent suppression of Akt pathway signaling, with transient activation of several Akt-associated readouts and inhibition of cyclin-dependent kinase signaling. The monophosphorylated metabolite TCN-P was the predominant intracellular active species, and adenosine kinase (ADK) was required for TCN-P generation and cytotoxicity. Proteome Integral Solubility Alteration profiling identified candidate TCN-P interactions involving nucleotide metabolism, DNA replication, and protein synthesis, associated with impaired purine biosynthesis, DNA damage, translational stress, and cell-cycle perturbation. Across ALL cell lines and primary samples, ADK levels correlated positively with TCN sensitivity, supporting ADK-dependent metabolism as a major determinant of therapeutic response. Together, these findings identify TCN as a metabolically activated antileukemic agent with broad antimetabolite activity and nominate ADK as a potential predictive biomarker for precision therapy in ALL.
SN - 2397-768X
ER -