Molecular determinants of drug response in TNBC cell lines

Purpose: There is a need for biomarkers of drug efficacy for targeted therapies in triple-negative breast Cancer (TNBC). As a step toward this, we identify multi-omic molecular determinants of anti-TNBC efficacy in cell lines for a panel of oncology drugs.

Methods: Using 23 TNBC cell lines, drug sensitivity scores (DSS₃) were determined using a panel of investigational drugs and drugs approved for Other indications. Molecular readouts were generated for each cell line using RNA Sequencing, RNA targeted panels, DNA Sequencing, and functional proteomics. DSS₃ values were correlated with molecular readouts using a FDR-corrected significance cutoff of p* < 0.05 and yielded molecular determinant panels that predict anti-TNBC efficacy.

Results: Six molecular determinant panels were obtained from 12 drugs we prioritized based on their efficacy. Determinant panels were largely devoid of DNA mutations of the targeted pathway. Molecular determinants were obtained by correlating DSS₃ with molecular readouts. We found that co-inhibiting molecular correlate pathways leads to robust synergy across many cell lines.

Conclusions: These findings demonstrate an integrated method to identify biomarkers of drug efficacy in TNBC where DNA predictions correlate poorly with drug response. Our work outlines a framework for the identification of novel molecular determinants and optimal companion drugs for combination therapy based on these correlates.