Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nature genetics, 2020-04, Vol.52 (4), p.408-417

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.