Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer.
Kevin H LinJustine C RutterAbigail XieBryann PardieuEmily T WinnReinaldo Dal BelloAntoine ForgetRaphael ItzyksonYeong-Ran AhnZiwei DaiRaiyan T SobhanGrace R AndersonKatherine R SingletonAmy E DeckerPeter S WinterJason W LocasaleLorin CrawfordAlexandre PuissantKris C WoodPublished in: Nature genetics (2020)
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.
Keyphrases
- drug induced
- liver injury
- genome wide
- papillary thyroid
- transcription factor
- crispr cas
- physical activity
- body composition
- squamous cell
- dna methylation
- gene expression
- genome editing
- cell proliferation
- clinical trial
- induced apoptosis
- squamous cell carcinoma
- fluorescent probe
- emergency department
- acute lymphoblastic leukemia
- endoplasmic reticulum stress
- double blind
- human health
- study protocol
- loop mediated isothermal amplification