A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia
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Published:2023-02-14
Issue:4
Volume:24
Page:3830
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Nasimian Ahmad12, Al Ashiri Lina12, Ahmed Mehreen12, Duan Hongzhi12, Zhang Xiaoyue12, Rönnstrand Lars123, Kazi Julhash U.12ORCID
Affiliation:
1. Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 22381 Lund, Sweden 2. Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, 22184 Lund, Sweden 3. Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, 22185 Lund, Sweden
Abstract
Despite incredible progress in cancer treatment, therapy resistance remains the leading limiting factor for long-term survival. During drug treatment, several genes are transcriptionally upregulated to mediate drug tolerance. Using highly variable genes and pharmacogenomic data for acute myeloid leukemia (AML), we developed a drug sensitivity prediction model for the receptor tyrosine kinase inhibitor sorafenib and achieved more than 80% prediction accuracy. Furthermore, by using Shapley additive explanations for determining leading features, we identified AXL as an important feature for drug resistance. Drug-resistant patient samples displayed enrichment of protein kinase C (PKC) signaling, which was also identified in sorafenib-treated FLT3-ITD-dependent AML cell lines by a peptide-based kinase profiling assay. Finally, we show that pharmacological inhibition of tyrosine kinase activity enhances AXL expression, phosphorylation of the PKC-substrate cyclic AMP response element binding (CREB) protein, and displays synergy with AXL and PKC inhibitors. Collectively, our data suggest an involvement of AXL in tyrosine kinase inhibitor resistance and link PKC activation as a possible signaling mediator.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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