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Zinc-finger Nuclease Enhanced Gene Targeting in Human Embryonic Stem Cells
Published on: August 23, 2014
Genome-wide screen for anticancer drug resistance in haploid human embryonic stem cells
Emanuel Segal1,2, Jonathan Nissenbaum1,3, Mordecai Peretz1
1The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
Abstract:
Anticancer drugs are at the frontline of cancer therapy. However, innate resistance to these drugs occurs in one-third to one-half of patients, exposing them to the side effects of these drugs with no meaningful benefit. To identify the genes and pathways that confer resistance to such therapies, we performed a genome-wide screen in haploid human embryonic stem cells (hESCs). These cells possess the advantage of having only one copy of each gene, harbour a normal karyotype, and lack any underlying point mutations. We initially show a close correlation between the potency of anticancer drugs in cancer cell lines to those in hESCs. We then exposed a genome-wide loss-of-function library of mutations in all protein-coding genes to 10 selected anticancer drugs, which represent five different mechanisms of drug therapies. The genetic screening enabled us to identify genes and pathways which can confer resistance to these drugs, demonstrating several common pathways. We validated a few of the resistance-conferring genes, demonstrating a significant shift in the effective drug concentrations to indicate a drug-specific effect to these genes. Strikingly, the p53 signalling pathway seems to induce resistance to a large array of anticancer drugs. The data shows dramatic effects of loss of p53 on resistance to many but not all drugs, calling for clinical evaluation of mutations in this gene prior to anticancer therapy.
Insights
Identifying genes that cause anticancer drug resistance is crucial. A genome-wide screen in human embryonic stem cells (hESCs) revealed key pathways, including the p53 signaling pathway, that impact drug efficacy.
Area of Science:
- Genetics
- Cancer Biology
- Pharmacology
Background:
- Innate resistance to anticancer drugs affects 33-50% of patients, leading to ineffective treatment and side effects.
- Identifying genetic factors contributing to drug resistance is essential for improving cancer therapy outcomes.
Purpose of the Study:
- To conduct a genome-wide screen to identify genes and pathways conferring resistance to anticancer drugs.
- To investigate the role of the p53 signaling pathway in mediating resistance to a broad spectrum of anticancer therapies.
Main Methods:
- Utilized haploid human embryonic stem cells (hESCs) for a genome-wide loss-of-function screen.
- Exposed hESCs with mutations in all protein-coding genes to 10 anticancer drugs representing five distinct mechanisms.
- Validated identified resistance-conferring genes and assessed drug-specific effects on drug concentrations.
Main Results:
- Identified multiple genes and common pathways conferring resistance to anticancer drugs.
- Demonstrated significant shifts in effective drug concentrations for validated resistance genes, indicating drug-specific effects.
- Observed that the p53 signaling pathway dramatically influences resistance to a wide range of anticancer drugs.
Conclusions:
- The study identified novel genetic determinants of anticancer drug resistance using a genome-wide screen in hESCs.
- The p53 signaling pathway plays a significant role in modulating resistance to numerous anticancer drugs, suggesting its clinical relevance.
- Clinical evaluation of p53 mutations prior to anticancer therapy may be warranted to predict treatment response.
