Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer

• Published in: Nature genetics Vol. 52; no. 4; pp. 408 - 417
• Main Authors: Lin, Kevin H., Rutter, Justine C., Xie, Abigail, Pardieu, Bryann, Winn, Emily T., Bello, Reinaldo Dal, Forget, Antoine, Itzykson, Raphael, Ahn, Yeong-Ran, Dai, Ziwei, Sobhan, Raiyan T., Anderson, Gray R., Singleton, Katherine R., Decker, Amy E., Winter, Peter S., Locasale, Jason W., Crawford, Lorin, Puissant, Alexandre, Wood, Kris C.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2020; Nature Publishing Group
• Subjects: 38; 631/208; 631/208/191; 631/67; 631/67/1990; 631/67/1990/283/1897; 64; 96/2; 96/95; Acute myeloid leukemia; Adaptation; Adaptation, Physiological - genetics; Agriculture; Animal Genetics and Genomics; Animals; Bcl-2 protein; Biological Evolution; Biomedicine; Cancer; Cancer Research; Cancer therapies; Cell Line; Cell Line, Tumor; Chemotherapy; Chemotherapy, Combination; CRISPR; CRISPR-Cas Systems - genetics; Datasets; Drug dependence; Drug development; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug targeting; Environment; Environmental changes; Evolution; Fitness; Gene Function; Genes; Genetic aspects; Genetic Fitness - genetics; Genetic Pleiotropy - genetics; HEK293 Cells; HL-60 Cells; Human Genetics; Humans; Hypersensitivity; Kinases; Leukemia; Libraries; Methods; Mice; Myc protein; Myeloid leukemia; Neoplasms - genetics; Nuclear Proteins - genetics; Phenotype; Pleiotropy; Principal components analysis; Quantitative Trait Loci - genetics; Reproductive fitness; Tradeoffs; Transcription Factors - genetics; Traps; Xenografts; Xenotransplantation; United States
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-020-0590-9

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. CRISPR–Cas9 knockout screens in chemotherapy-treated acute myeloid leukemia cells help map the drug-dependent genetic basis of fitness trade-offs (antagonistic pleiotropy) for the design of evolutionary traps that target drug resistance in cancer.