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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Lin, KH; Rutter, JC; Xie, A; Pardieu, B; Winn, ET; Bello, RD; Forget, A; Itzykson, R; Ahn, Y-R; Dai, Z; Sobhan, RT; Anderson, GR; Singleton, KR; Decker, AE; Winter, PS; Locasale, JW; Crawford, L; Puissant, A; Wood, KC

Published Date

  • April 2020

Published In

Volume / Issue

  • 52 / 4

Start / End Page

  • 408 - 417

PubMed ID

  • 32203462

Pubmed Central ID

  • 32203462

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

International Standard Serial Number (ISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/s41588-020-0590-9

Language

  • eng