TY - JOUR
T1 - Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach
AU - Petrosyan, Varduhi
AU - Dobrolecki, Lacey E.
AU - Thistlethwaite, Lillian
AU - Lewis, Alaina N.
AU - Sallas, Christina
AU - Srinivasan, Ramakrishnan R.
AU - Lei, Jonathan T.
AU - Kovacevic, Vladimir
AU - Obradovic, Predrag
AU - Ellis, Matthew J.
AU - Osborne, C. Kent
AU - Rimawi, Mothaffar F.
AU - Pavlick, Anne
AU - Shafaee, Maryam Nemati
AU - Dowst, Heidi
AU - Jain, Antrix
AU - Saltzman, Alexander B.
AU - Malovannaya, Anna
AU - Marangoni, Elisabetta
AU - Welm, Alana L.
AU - Welm, Bryan E.
AU - Li, Shunqiang
AU - Wulf, Gerburg M.
AU - Sonzogni, Olmo
AU - Huang, Chen
AU - Vasaikar, Suhas
AU - Hilsenbeck, Susan G.
AU - Zhang, Bing
AU - Milosavljevic, Aleksandar
AU - Lewis, Michael T.
N1 - Publisher Copyright:
© 2022
PY - 2023/1/20
Y1 - 2023/1/20
N2 - 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.
AB - 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.
KW - Cancer
KW - Immune response
KW - Omics
UR - http://www.scopus.com/inward/record.url?scp=85144867364&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.105799
DO - 10.1016/j.isci.2022.105799
M3 - Article
C2 - 36619972
AN - SCOPUS:85144867364
SN - 2589-0042
VL - 26
JO - iScience
JF - iScience
IS - 1
M1 - 105799
ER -