ABSTRACT
Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, CERS1, ST8SIA2, KIF24, PARPBP). CTD/WGCNA multigene biomarkers are predictive in PDX datasets (RNAseq and Affymetrix) for both taxane- (docetaxel or paclitaxel) and platinum-based (carboplatin or cisplatin) response, thereby demonstrating cross-expression platform and cross-drug class robustness. These biomarkers were also predictive in clinical datasets, thus demonstrating translational potential.
ABSTRACT
Extraction of subsets of highly connected nodes ("communities" or modules) is a standard step in the analysis of complex social and biological networks. We here consider the problem of finding a relatively small set of nodes in two labeled weighted graphs that is highly connected in both. While many scoring functions and algorithms tackle the problem, the typically high computational cost of permutation testing required to establish the p-value for the observed pattern presents a major practical obstacle. To address this problem, we here extend the recently proposed CTD ("Connect the Dots") approach to establish information-theoretic upper bounds on the p-values and lower bounds on the size and connectedness of communities that are detectable. This is an innovation on the applicability of CTD, broadening its use to pairs of graphs.
