A Network Approach to Identify Biomarkers of Differential Chemotherapy Response Using Patient-Derived Xenografts of Triple-Negative Breast Cancer

Triple negative breast cancer (TNBC) is a highly heterogeneous set of diseases that has, until recently, lacked any FDA-approved, molecularly targeted therapeutics. Thus, systemic chemotherapy regimens remain the standard of care for many. Unfortunately, even combination chemotherapy is ineffective for many TNBC patients, and side-effects can be severe or lethal. Identification of predictive biomarkers for chemotherapy response would allow for the prospective selection of responsive patients, thereby maximizing efficacy and minimizing unwanted toxicities. Here, we leverage a cohort of TNBC PDX models with responses to single-agent docetaxel or carboplatin to identify biomarkers predictive for differential response to these two drugs. To demonstrate their ability to function as a preclinical cohort, PDX were molecularly characterized using whole-exome DNA sequencing, RNAseq transcriptomics, and mass spectrometry-based total proteomics to show proteogenomic consistency with TCGA and CPTAC clinical samples. Focusing first on the transcriptome, we describe a network-based computational approach to identify candidate epithelial and stromal biomarkers of response to carboplatin ( MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ ) and docetaxel ( ITGA7, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP) . Biomarker panels are predictive in PDX expression datasets (RNAseq and Affymetrix) for both taxane (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating both cross expression platform and cross drug class robustness. Biomarker panels were also predictive in clinical datasets with response to cisplatin or paclitaxel, thus demonstrating translational potential of PDX-based preclinical trials. This network-based approach is highly adaptable and can be used to evaluate biomarkers of response to other agents. ### Competing Interest Statement M.T.L is a Founder of, and an uncompensated Manager in StemMed Holdings L.L.C., an uncompensated Limited Partner in StemMed Ltd., and is a Founder of and equity stake holder in Tvardi Therapeutics. L.D. is a compensated employee of StemMed Ltd. Selected BCM PDX models described herein are exclusively licensed to StemMed Ltd. resulting in tangible property royalties to M.T.L. and L.D. University of Utah may license the HCI PDX models described herein to for-profit companies, which may result in tangible property royalties to A.L.W. and B.E.W. Washington University has licensed selected PDX to Envigo which results in tangible property royalties to S.L. He also received research funding from Pfizer, Takeda Oncology, Zenopharm, independent of this project. S.L has received license fees from Envigo. He received research funding from Pfizer, Takeda Oncology, Zenopharm, outside of this project. O.S is a compensated employee of, and equity stake holder in, Bluebird Bio.