Molecular determinants of drug response in TNBC cell lines
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.
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.
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.
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.
KeywordsTriple-negative breast cancer Molecular determinants Combination therapy Sequencing Functional proteomics
We kindly thank Rork Kuick (University of Michigan) for his insight on statistical analysis and careful editing of this manuscript. We thank the MD Anderson RPPA core for protein analysis, TIGEM in Naples, Italy for RNA sequencing, and the University of Michigan sequencing core for DNA sequencing.
Study concept and design: M.B.S., N.M.M. Acquisition of data: N.M.M., N.M.V., E.J.L., L.W.B. Drafting the manuscript: N.M.M., J.A.Y., M.B.S., S.D.M. Analysis and interpretation of data: N.M.M., M.B.S., P.J.L, J.P.L., S.D.M. Experimentation: N.M.M., N.M.V., E.J.L., L.W.B. Statistical analysis: N.M.M., P.U.L., J.P.L. Administrative, technical, or material support: J.A.Y., A.M. Study supervision: M.B.S., S.D.M. All authors reviewed and approved the final version of the manuscript.
This research was supported by the National Institutes of Health (1R21CA218498 to M.B.S. and S.D.M.), the Breast Cancer Research Foundation (to S.D.M.), Tempting Tables (to S.D.M.), The Rose Run (to S.D.M.), and the Kathy Bruk Pearce Research Fund of the University of Michigan Rogel Cancer Center (to M.B.S.).
Compliance with ethical standards
Conflicts of interest
All authors declare that they have no conflicts of interest related to this work.
Research involving human and animal participants
This article does not contain any studies with human participants or animals performed by any of the authors.
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