دورية أكاديمية
Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer.
| العنوان: | Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer. |
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| المؤلفون: | Lin KH; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Rutter JC; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Xie A; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Pardieu B; Université de Paris, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, Paris, France., Winn ET; Division of Applied Mathematics, Brown University, Providence, RI, USA., Bello RD; Université de Paris, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, Paris, France.; Department of Hematology, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Forget A; Université de Paris, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, Paris, France., Itzykson R; Université de Paris, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, Paris, France.; Service Hématologie Adultes, AP-HP, Hôpital Saint-Louis, Paris, France., Ahn YR; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Dai Z; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Sobhan RT; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Anderson GR; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Singleton KR; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Decker AE; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Winter PS; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Locasale JW; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., Crawford L; Department of Biostatistics, Brown University, Providence, RI, USA., Puissant A; Université de Paris, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, Paris, France. alexandre.puissant@inserm.fr., Wood KC; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA. kris.wood@duke.edu. |
| المصدر: | Nature genetics [Nat Genet] 2020 Apr; Vol. 52 (4), pp. 408-417. Date of Electronic Publication: 2020 Mar 16. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York, NY : Nature Pub. Co., c1992- |
| مواضيع طبية MeSH: | Drug Resistance, Neoplasm/*genetics , Genetic Pleiotropy/*genetics , Neoplasms/*genetics, Adaptation, Physiological/genetics ; Animals ; Biological Evolution ; CRISPR-Cas Systems/genetics ; Cell Line ; Cell Line, Tumor ; Environment ; Genetic Fitness/genetics ; HEK293 Cells ; HL-60 Cells ; Humans ; Mice ; Nuclear Proteins/genetics ; Phenotype ; Quantitative Trait Loci/genetics ; Transcription Factors/genetics |
| مستخلص: | Local adaptation directs populations towards environment-specific fitness maxima through acquisition of positively selected traits. However, rapid environmental changes can identify hidden fitness trade-offs that turn adaptation into maladaptation, resulting in evolutionary traps. Cancer, a disease that is prone to drug resistance, is in principle susceptible to such traps. We therefore performed pooled CRISPR-Cas9 knockout screens in acute myeloid leukemia (AML) cells treated with various chemotherapies to map the drug-dependent genetic basis of fitness trade-offs, a concept known as antagonistic pleiotropy (AP). We identified a PRC2-NSD2/3-mediated MYC regulatory axis as a drug-induced AP pathway whose ability to confer resistance to bromodomain inhibition and sensitivity to BCL-2 inhibition templates an evolutionary trap. Across diverse AML cell-line and patient-derived xenograft models, we find that acquisition of resistance to bromodomain inhibition through this pathway exposes coincident hypersensitivity to BCL-2 inhibition. Thus, drug-induced AP can be leveraged to design evolutionary traps that selectively target drug resistance in cancer. |
| التعليقات: | Comment in: Nat Genet. 2020 Apr;52(4):361-362. doi: 10.1038/s41588-020-0608-3. (PMID: 32246131) |
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| معلومات مُعتمدة: | F30 CA206348 United States CA NCI NIH HHS; F31 CA195967 United States CA NCI NIH HHS; R01 CA207083 United States CA NCI NIH HHS; P30 CA014236 United States CA NCI NIH HHS; T32 GM007171 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 0 (Nuclear Proteins) 0 (Transcription Factors) |
| تواريخ الأحداث: | Date Created: 20200324 Date Completed: 20200626 Latest Revision: 20240922 |
| رمز التحديث: | 20240922 |
| مُعرف محوري في PubMed: | PMC7398704 |
| DOI: | 10.1038/s41588-020-0590-9 |
| PMID: | 32203462 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1546-1718 |
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| DOI: | 10.1038/s41588-020-0590-9 |