A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia
(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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- author
- Nasimian, Ahmad LU ; Al Ashiri, Lina LU ; Ahmed, Mehreen LU ; Duan, Hongzhi LU ; Zhang, Xiaoyue LU ; Rönnstrand, Lars LU and Kazi, Julhash U LU
- organization
- publishing date
- 2023-02-14
- 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}}, }