Integrated single-dose kinome profiling data is predictive of cancer cell line sensitivity to kinase inhibitors

• Published in: PeerJ (San Francisco, CA) CA), 2023-11, Vol.11, p.e16342, Article e16342
• Main Authors: Joisa, Chinmaya U, Chen, Kevin A, Berginski, Matthew E, Golitz, Brian T, Jenner, Madison R, Herrera Loeza, Gabriela, Yeh, Jen Jen, Gomez, Shawn M
• Format: Article
• Language: English
• Subjects: Analysis; Cancer; Cancer therapies; Cell Line; Cell phenotypes; Clinical trials; Datasets; Drug dosages; Drug response; Enzyme inhibitors; Gene expression; Humans; Kinase inhibitor treatment; Kinases; Machine learning; Mathematical models; Neoplasms - drug therapy; Pancreatic cancer; Phenotypes; Phosphotransferases - pharmacology; Predictive modeling; Protein Kinase Inhibitors - pharmacology; Protein kinases; Proteins; Signal Transduction; Tumor cell lines
• ISSN: 2167-8359; 2167-8359
• DOI: 10.7717/peerj.16342

Protein kinase activity forms the backbone of cellular information transfer, acting both individually and as part of a broader network, the kinome. Their central role in signaling leads to kinome dysfunction being a common driver of disease, and in particular cancer, where numerous kinases have been identified as having a causal or modulating role in tumor development and progression. As a result, the development of therapies targeting kinases has rapidly grown, with over 70 kinase inhibitors approved for use in the clinic and over double this number currently in clinical trials. Understanding the relationship between kinase inhibitor treatment and their effects on downstream cellular phenotype is thus of clear importance for understanding treatment mechanisms and streamlining compound screening in therapy development. In this work, we combine two large-scale kinome profiling data sets and use them to link inhibitor-kinome interactions with cell line treatment responses (AUC/IC ). We then built computational models on this data set that achieve a high degree of prediction accuracy (R of 0.7 and RMSE of 0.9) and were able to identify a set of well-characterized and understudied kinases that significantly affect cell responses. We further validated these models experimentally by testing predicted effects in breast cancer cell lines and extended the model scope by performing additional validation in patient-derived pancreatic cancer cell lines. Overall, these results demonstrate that broad quantification of kinome inhibition state is highly predictive of downstream cellular phenotypes.