An Exploration of Ancient Kinases and a Meta-Analysis of the Modern Use of Tyrosine Kinase Inhibitors in the Literature

open_access
Open Access
Author:
Abello, Kerry
Area of Honors:
Biomedical Engineering
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
Justin R Pritchard, Thesis Supervisor
Justin Lee Brown, Thesis Honors Advisor
Keywords:
Kinases
Tyrosine Kinases
Src
Abl
Cancer
Tyrosine Kinase Inhibitor
Imatinib
Pharmacokinetics
Serum Binding
Protein Binding
Abstract:
Protein kinases regulate the majority of cellular pathways and therefore play a fundamental role in human health, as they are implicated in a variety of human diseases, most notably, cancer. [1][2] Specifically, aberrant tyrosine kinase activity has been found to cause a variety of cancers. [2] For this reason, tyrosine kinases are a commonly used drug target in modern cancer therapy, characterizing the class of drugs known as Tyrosine Kinase Inhibitors (TKIs). Studying the ancestors of modern, oncogenic tyrosine kinases can provide a better understanding of the evolution of their oncogenic activity. [3] In this study, we clone reconstructed ancient kinase genes into vectors and perform cell-based transformation experiments to test the oncogenic potential of these kinases. We found that two modern kinases and their most recent common ancestor were transforming, while two intermediates were non-transforming. Additionally, we explore the clinical repurposing of TKIs, which is frequently unsuccessful [4] and begins with justification from preclinical in vitro evidence. We perform a systematic review of preclinical literature to analyze the extent of pharmacokinetic consideration in in vitro experiment design when making translational claims about TKIs. We found that the majority of preclinical TKI studies do not consider pharmacokinetics or serum binding and use clinically irrelevant drug concentrations in vitro. We also performed a serum shift experiment and found that the presence of serum directly prevents drug from reaching its target. Overall, we conclude that oncogenic potential seems to be a fundamental characteristic of kinases since their emergence, a property that may have been lost and later regained. From our meta- analysis, we conclude that a common source of clinical repurposing failure is lack of pharmacokinetic and serum binding consideration in the in vitro experiment design of preclinical studies.