Genomic Profiling in CEPH Cell Lines Distinguishes between the Camptothecins and Indenoisoquinolines

Abstract

We have attempted to use a familial genetics strategy to study mechanisms of Topoisomerase 1 (Top1) inhibition. Investigations have steadily been chipping away at the pathways involved in cellular response following Top1 inhibition for more than 20 years. Our system-wide approach, which phenotypes a collection of genotyped human cell lines for sensitivity to compounds, interrogates all genes and molecular pathways simultaneously. Previously, we characterized the in vitro sensitivity of fifteen families of CEPH cell lines (n = 142) to nine camptothecin analogues. Linkage analysis revealed a pattern of seven quantitative trait loci (QTLs) shared by all of the camptothecins. To identify which, if any, QTLs are related to the general mechanism of Top1 inhibition or should be considered camptothecin-specific, we characterized the in vitro sensitivity of the same panel of CEPH cell lines to the indenisoquinolones, a structurally distinct class of Top 1 inhibitors. Four QTLs on chromosomes 1, 5, 11, and 16 were shared by both the camptothecins and the indenoisoquinolines and are considered associated with the general mechanism of Top1 inhibition. The remaining three QTLs (chromosomes 6 and 20) are considered specific to camptothecin-induced cytotoxicity. Finally, eight QTLs were identified which were unique to the indenoisoquinolines.

Analysis of innate and acquired resistance to anti-CD20 antibodies in malignant and nonmalignant B cells

“…Still, future validation of our findings in non-EBV immortalized cells will be essential. These potential limitations are likely to be outweighed by the capacity now, with the findings from this work, for the high-throughput study of a large number of nonmalignant B-cells for large-scale studies as has been done with other cytotoxic agents (Hartford et al, 2009; Huang et al, 2011; Peters et al, 2011; Watson et al, 2011). The ability to detect and compare both innate and acquired resistance to anti-CD20 antibodies in vitro in nonmalignant immortalized B-cells now provides a powerful new reagent for high-throughput genetic studies to further define and delineate the factors underlying both rituximab and ofatumumab resistance.…”

Genome-Wide Association and Pharmacological Profiling of 29 Anticancer Agents Using Lymphoblastoid Cell Lines

“…For example, it has been used to assess the heritability of a number of dose-response outcomes [4, 12], and to successfully detect genetic associations of clinical relevance, with notable instances being in head and neck cancer [13] and temozolomide response [10]. Additionally, similarity in dose response has been seen across drugs within a single drug family [14], reinforcing the potential of the model to categorize responses as a function of mechanism of action. The use of the LCL model system in pharmacogenomics has been reviewed elsewhere [5].…”

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

“…Just as there is variability in patients’ response to single drugs, it is generally accepted that individual response to combination therapy can be variable, and the underlying reasons for this are not well understood. It has been well established in lymphoblastoid cell lines (LCLs) that dose response to single drug exposure has a genetic component; thus, an underlying genetic etiology of drug synergy could be a viable mechanism of interindividual variation in the synergistic response (Peters et al, 2011; Watson et al, 2011; Abdo et al, 2015).…”

“…Lymphoblastoid cell lines are a highly successful model for dissecting the genetic etiology of cancer drug response, including estimating the heritability of drug response traits and performing both linkage and association mapping to identify putative regions and genes that explain variability in dose response (Watson et al, 2011; Moen et al, 2012; Wheeler et al, 2013; Niu et al, 2016; Jack et al, 2018). As reviewed here, the LCL model system has resulted in a number of translatable successes (Jack et al, 2014).…”