In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy.
Meiou DaiGang YanNi WangGirija DaliahAshlin M EdickSophie PouletJulien BoudreaultSuhad AliSergio A BurgosJean-Jacques LebrunPublished in: Nature communications (2021)
Triple negative breast cancer (TNBC) patients exhibit poor survival outcomes and lack effective targeted therapies. Using unbiased in vivo genome-wide CRISPR screening, we interrogated cancer vulnerabilities in TNBC and identified an interplay between oncogenic and tumor suppressor pathways. This study reveals tumor regulatory functions for essential components of the mTOR and Hippo pathways in TNBC. Using in vitro drug matrix synergy models and in vivo patient-derived xenografts, we further establish the therapeutic relevance of our findings and show that pharmacological inhibition of mTORC1/2 and oncoprotein YAP efficiently reduces tumorigenesis in TNBC. At the molecular level, we find that while verteporfin-induced YAP inhibition leads to apoptosis, torin1-mediated mTORC1/2 inhibition promotes macropinocytosis. Torin1-induced macropinocytosis further facilitates verteporfin uptake, thereby greatly enhancing its pro-apoptotic effects in cancer cells. Overall, our study underscores the power and robustness of in vivo CRISPR genome-wide screens in identifying clinically relevant and innovative therapeutic modalities in cancer.
Keyphrases
- genome wide
- dna methylation
- copy number
- combination therapy
- papillary thyroid
- end stage renal disease
- cell death
- high glucose
- diabetic rats
- chronic kidney disease
- transcription factor
- cell proliferation
- high throughput
- newly diagnosed
- cancer therapy
- oxidative stress
- drug induced
- genome editing
- endoplasmic reticulum stress
- endothelial cells
- drug delivery
- squamous cell carcinoma
- signaling pathway
- peritoneal dialysis