RT Journal Article
SR Electronic
T1 Kinome state is predictive of cell viability in pancreatic cancer tumor and stroma cell lines
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.21.451515
DO 10.1101/2021.07.21.451515
A1 Matthew E. Berginski
A1 Madison R. Jenner
A1 Chinmaya U. Joisa
A1 Silvia G. Herrera Loeza
A1 Brian T. Golitz
A1 Matthew B. Lipner
A1 John R. Leary
A1 Naim U. Rashid
A1 Gary L. Johnson
A1 Jen Jen Yeh
A1 Shawn M. Gomez
YR 2021
UL http://biorxiv.org/content/early/2021/10/19/2021.07.21.451515.abstract
AB Numerous aspects of cellular signaling are regulated by the kinome – the network of over 500 protein kinases that guides and modulates information transfer throughout the cell. The key role played by both individual kinases and assemblies of kinases organized into functional subnetworks leads to kinome dysregulation being a key driver of many diseases, particularly cancer. In the case of pancreatic ductal adenocarcinoma (PDAC), a variety of kinases and associated signaling pathways have been identified for their key role in the establishment of disease as well as its progression. However, the identification of additional relevant therapeutic targets has been slow and is further confounded by interactions between the tumor and the surrounding tumor microenvironment. Fundamentally, it is an open question as to the degree to which knowledge of the state of the kinome at the protein level is able to provide insight into the downstream phenotype of the cell.In this work, we attempt to link the state of the kinome, or kinotype, with cell viability in representative PDAC tumor and stroma cell lines. Through the application of both regression and classification models to independent kinome perturbation and kinase inhibitor cell screen data, we find that the inferred kinotype of a cell has a significant and predictive relationship with cell viability. While regression models perform poorly, we find that classification approaches are able to predict drug viability effects. We further find that models are able to identify a set of kinases whose behavior in response to perturbation drive the majority of viability responses in these cell lines. Using the models to predict new compounds with cell viability effects and not in the initial data set, we conducted a validation screen that confirmed the accuracy of the models. These results suggest that characterizing the state of the protein kinome provides significant opportunity for better understanding signaling behavior and downstream cell phenotypes, as well as providing insight into the broader design of potential therapy design for PDAC.Competing Interest StatementThe authors have declared no competing interest.