SIMD: Synergistic integration mutualistic platform based on single-cell and proteotranscriptomics for drug...

Area of Science:

• Oncology
• Computational Biology
• Genomics

Background:

• Breast cancer exhibits significant tumor heterogeneity, complicating treatment strategies.
• Existing drug repositioning methods often overlook the dynamic interplay between protein and transcriptomic data at the single-cell level.

Purpose of the Study:

• To introduce a synergistic integration platform for drug repositioning (SIMD) in breast cancer.
• To leverage single-cell and proteotranscriptomics to identify novel drug candidates by considering molecular dynamics and tumor heterogeneity.

Main Methods:

• Developed the anti-correlated proteotranscriptome perturbation score (ACPS) to measure negative correlations between molecular signatures.
• Utilized perturbagen repositioning scoring and single-cell RNA sequencing (scRNA-seq) data (PPNE) to rank potential drug candidates.
• Validated top-ranked drug candidates by assessing their impact on breast cancer cell line viability.

Main Results:

• The SIMD platform successfully prioritized drug candidates for breast cancer.
• Many top-ranked candidates have prior clinical trial involvement for various cancers.
• Experimental validation demonstrated significant reductions in cell viability for most prioritized perturbagens across breast cancer cell lines.
• Identified overexpressed phosphorylation sites in AKT1 and PI3K genes, suggesting buparlisib's potential efficacy across diverse breast cancer subtypes, including triple-negative breast cancer.

Conclusions:

• The SIMD platform offers a novel approach for drug repositioning in breast cancer.
• The findings support buparlisib's potential therapeutic role in breast cancer by targeting the PI3K pathway.
• This integrated omics strategy holds promise for advancing precision oncology and personalized medicine.