University of Oulu

Elmadani, M., Khan, S., Tenhunen, O., Magga, J., Aittokallio, T., Wennerberg, K., Kerkelä, R. (2019) Novel Screening Method Identifies PI3Kα, mTOR, and IGF1R as Key Kinases Regulating Cardiomyocyte Survival. Journal of the american heart association. cardiovascular and cerebrovascular disease, 8 (21), e013018. doi:10.1161/JAHA.119.013018

Novel screening method identifies PI3Kα, mTOR, and IGF1R as key kinases regulating cardiomyocyte survival

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Author: Elmadani, Manar1; Khan, Suleiman2; Tenhunen, Olli3;
Organizations: 1Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Finland
2Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland
3Department of Oncology and Radiotherapy, Oulu University Hospital, University of Oulu, Finland
4Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019121146676
Language: English
Published: John Wiley & Sons, 2019
Publish Date: 2019-12-11
Description:

Abstract

Background: Small molecule kinase inhibitors (KIs) are a class of agents currently used for treatment of various cancers. Unfortunately, treatment of cancer patients with some of the KIs is associated with cardiotoxicity, and there is an unmet need for methods to predict their cardiotoxicity. Here, we utilized a novel computational method to identify protein kinases crucial for cardiomyocyte viability.

Methods and Results: One hundred forty KIs were screened for their toxicity in cultured neonatal cardiomyocytes. The kinase targets of KIs were determined based on integrated data from binding assays. The key kinases mediating the toxicity of KIs to cardiomyocytes were identified by using a novel machine learning method for target deconvolution that combines the information from the toxicity screen and from the kinase profiling assays. The top kinases identified by the model were phosphoinositide 3‐kinase catalytic subunit alpha, mammalian target of rapamycin, and insulin‐like growth factor 1 receptor. Knockdown of the individual kinases in cardiomyocytes confirmed their role in regulating cardiomyocyte viability.

Conclusions: Combining the data from analysis of KI toxicity on cardiomyocytes and KI target profiling provides a novel method to predict cardiomyocyte toxicity of KIs.

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Series: Journal of the American Heart Association
ISSN: 2047-9980
ISSN-E: 2047-9980
ISSN-L: 2047-9980
Volume: 8
Issue: 21
Article number: e013018
DOI: 10.1161/JAHA.119.013018
OADOI: https://oadoi.org/10.1161/JAHA.119.013018
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Subjects:
Funding: This work was supported by Academy of Finland grants 131020 and 297094 to Kerkelä and 268505 to Magga, and 296516 to Khan, and by Finnish Foundation for Cardiovascular Research (to Elmadani, Magga, and Kerkelä).
Academy of Finland Grant Number: 131020
297094
268505
Detailed Information: 131020 (Academy of Finland Funding decision)
297094 (Academy of Finland Funding decision)
268505 (Academy of Finland Funding decision)
Copyright information: © The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
  https://creativecommons.org/licenses/by-nc-nd/4.0/