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A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia

Nasimian, Ahmad LU ; Al Ashiri, Lina LU orcid ; Ahmed, Mehreen LU ; Duan, Hongzhi LU ; Zhang, Xiaoyue LU ; Rönnstrand, Lars LU orcid and Kazi, Julhash U LU orcid (2023) In International Journal of Molecular Sciences 24(4).
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... (More)

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.

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Please use this url to cite or link to this publication:
author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
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
in
International Journal of Molecular Sciences
volume
24
issue
4
article number
3830
publisher
MDPI AG
external identifiers
  • scopus:85148943929
  • pmid:36835239
ISSN
1422-0067
DOI
10.3390/ijms24043830
language
English
LU publication?
yes
id
840acd1e-c345-48b4-8a37-c167184d0b94
date added to LUP
2023-03-09 15:30:31
date last changed
2024-04-18 11:19:51
@article{840acd1e-c345-48b4-8a37-c167184d0b94,
  abstract     = {{<p>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.</p>}},
  author       = {{Nasimian, Ahmad and Al Ashiri, Lina and Ahmed, Mehreen and Duan, Hongzhi and Zhang, Xiaoyue and Rönnstrand, Lars and Kazi, Julhash U}},
  issn         = {{1422-0067}},
  keywords     = {{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}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{4}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia}},
  url          = {{http://dx.doi.org/10.3390/ijms24043830}},
  doi          = {{10.3390/ijms24043830}},
  volume       = {{24}},
  year         = {{2023}},
}