Synergistic Chemotherapy Drug Response Is a Genetic Trait in Lymphoblastoid Cell Lines

Abstract

Lymphoblastoid cell lines (LCLs) are a highly successful model for evaluating the genetic etiology of cancer drug response, but applications using this model have typically focused on single drugs. Combination therapy is quite common in modern chemotherapy treatment since drugs often work synergistically, and it is an important progression in the use of the LCL model to expand work for drug combinations. In the present work, we demonstrate that synergy occurs and can be quantified in LCLs across a range of clinically important drug combinations. Lymphoblastoid cell lines have been commonly employed in association mapping in cancer pharmacogenomics, but it is so far untested as to whether synergistic effects have a genetic etiology. Here we use cell lines from extended pedigrees to demonstrate that there is a substantial heritable component to synergistic drug response. Additionally, we perform linkage mapping in these pedigrees to identify putative regions linked to this important phenotype. This demonstration supports the premise of expanding the use of the LCL model to perform association mapping for combination therapies.

Development of the InTelligence And Machine LEarning (TAME) Toolkit for Introductory Data Science, Chemical-Biological Analyses, Predictive Modeling, and Database Mining for Environmental Health Research

“…TAME Toolkit content and associated training modules were developed by experts in environmental health research and data science. These experts were selected to contribute to the TAME Toolkit based on the following qualifications: Dr. Kyle Roell is the lead Data Analyst for the Institute for Environmental Health Solutions at the University of North Carolina at Chapel Hill (UNC) and is an experienced software developer and programmer with expertise in bioinformatics and statistical genetics ( Zhang et al, 2017 ; Roell et al, 2019 ; Roell et al, 2021 ). Ms. Koval is a graduate student in the UNC Department of Environmental Sciences and Engineering and is contributing towards ongoing studies on human health and the environment ( Ring et al, 2021 ; Carberry et al, 2022 ).…”

Hydrogels and Hydrogel Nanocomposites: Enhancing Healthcare through Human and Environmental Treatment

“…[183][184][185][186][187][188][189][190][191][192] Among the most desirable outcomes is a synergistic effect, where the efficacy of multiple chemotherapeutics administered together is greater than the sum of the individual therapeutics administered independently. [193,194] Because of their intrinsic properties, hydrogels can be introduced by direct injection into the localized tumor area and have become the go-to drug delivery system for synergistic cancer treatment. Additionally, release kinetics can be easily tuned by adjusting polymer/water ratio.…”