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26.10.2019 | Preclinical study

Molecular determinants of drug response in TNBC cell lines

verfasst von: Nathan M. Merrill, Eric J. Lachacz, Nathalie M. Vandecan, Peter J. Ulintz, Liwei Bao, John P. Lloyd, Joel A. Yates, Aki Morikawa, Sofia D. Merajver, Matthew B. Soellner

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2020

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Abstract

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.

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Titel: Molecular determinants of drug response in TNBC cell lines
verfasst von: Nathan M. Merrill
Eric J. Lachacz
Nathalie M. Vandecan
Peter J. Ulintz
Liwei Bao
John P. Lloyd
Joel A. Yates
Aki Morikawa
Sofia D. Merajver
Matthew B. Soellner
Publikationsdatum: 26.10.2019
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 2/2020
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05473-9

Springer Medizin

Molecular determinants of drug response in TNBC cell lines