Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are...

Area of Science:

• Hematology
• Pharmacology
• Cancer Biology

Background:

• Innate drug sensitivity in healthy cells can guide anti-cancer therapy selection and predict off-target effects.
• Characterizing drug responses in major hematopoietic cell types is crucial for developing lineage-specific treatments.

Purpose of the Study:

• To map the diversity of drug responses across healthy hematopoietic cell types.
• To correlate drug sensitivity with proteomic and signaling profiles.
• To assess the predictive value of healthy cell drug responses for neoplastic cells.

Main Methods:

• Simultaneous assessment of sensitivity to 71 small molecules using multi-parametric flow cytometry.
• Proteomic and basal signaling profiling of major hematopoietic cell types.
• Unsupervised hierarchical clustering to identify distinct drug response patterns.

Main Results:

• Distinct drug responses were observed in healthy hematopoietic cell subsets, clustered by lineage.
• CD19+/B and CD56+/NK cells showed higher sensitivity to dexamethasone, venetoclax, and midostaurin; monocytes were more sensitive to trametinib.
• Healthy cell drug responses predicted responses in corresponding malignant cells, with lineage-specific effects of midostaurin noted.

Conclusions:

• Understanding healthy cell drug sensitivity offers a novel approach for precise anti-cancer therapy.
• This knowledge can help in avoiding off-target toxicities by predicting drug effects on healthy cells.
• Drug sensitivity profiling in healthy cells provides a foundation for personalized cancer treatment strategies.