WFRF:(Nasimian Ahmad)
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A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia
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- Nasimian, Ahmad (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Stem Cell Center,Division of stem cell research,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Al Ashiri, Lina (author)
- Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Molekylär cancerforskning,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Molecular Cancer Research,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Ahmed, Mehreen (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Stem Cell Center,Division of stem cell research,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- (creator_code:org_t)
- 2023-02-14
- 2023
- English.
- In: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 24:4
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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 headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Keyword
- Humans
- Sorafenib/therapeutic use
- Tyrosine Protein Kinase Inhibitors
- Mutation
- Protein Kinase Inhibitors/pharmacology
- Leukemia, Myeloid, Acute/genetics
- fms-Like Tyrosine Kinase 3/genetics
- Drug Resistance, Neoplasm/genetics
- Cell Line, Tumor
Publication and Content Type
- art (subject category)
- ref (subject category)
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- Nasimian, Ahmad
- Al Ashiri, Lina
- Ahmed, Mehreen
- Duan, Hongzhi
- Zhang, Xiaoyue
- Rönnstrand, Lars
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- Kazi, Julhash U
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