Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach

Varduhi Petrosyan; Lacey E Dobrolecki; Lillian Thistlethwaite; Alaina N Lewis; Christina Sallas; Ramakrishnan R Srinivasan; Jonathan T Lei; Vladimir Kovacevic; Predrag Obradovic; Matthew J Ellis; C Kent Osborne; Mothaffar F Rimawi; Anne Pavlick; Maryam Nemati Shafaee; Heidi Dowst; Antrix Jain; Alexander B Saltzman; Anna Malovannaya; Elisabetta Marangoni; Alana L Welm; Bryan E Welm; Shunqiang Li; Gerburg M Wulf; Olmo Sonzogni; Chen Huang; Suhas Vasaikar; Susan G Hilsenbeck; Bing Zhang; Aleksandar Milosavljevic; Michael T Lewis

doi:10.1016/j.isci.2022.105799

Identifying biomarkers of differential chemotherapy response in TNBC patient-derived xenografts with a CTD/WGCNA approach

iScience. 2022 Dec 12;26(1):105799. doi: 10.1016/j.isci.2022.105799. eCollection 2023 Jan 20.

Authors

Varduhi Petrosyan¹, Lacey E Dobrolecki², Lillian Thistlethwaite³, Alaina N Lewis², Christina Sallas², Ramakrishnan R Srinivasan², Jonathan T Lei², Vladimir Kovacevic⁴, Predrag Obradovic⁴, Matthew J Ellis^{2

5}, C Kent Osborne^{2

5}, Mothaffar F Rimawi^{2

5}, Anne Pavlick², Maryam Nemati Shafaee², Heidi Dowst⁵, Antrix Jain⁶, Alexander B Saltzman⁶, Anna Malovannaya^{5

7

6

8}, Elisabetta Marangoni⁹, Alana L Welm^{10

11}, Bryan E Welm^{12

11}, Shunqiang Li¹³, Gerburg M Wulf¹⁴, Olmo Sonzogni¹⁴, Chen Huang², Suhas Vasaikar², Susan G Hilsenbeck^{2

5}, Bing Zhang^{1

2

3}, Aleksandar Milosavljevic^{1

3}, Michael T Lewis^{2

5

8

15}

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
² Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
³ Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ School of Electrical Engineering, University of Belgrade, Belgrade, Serbia.
⁵ Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁸ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
⁹ Curie Institute, Paris, France.
¹⁰ Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
¹¹ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
¹² Department of Surgery, University of Utah, Salt Lake City, UT 84112, USA.
¹³ Division of Oncology, Washington University, St. Louis, MO 63130, USA.
¹⁴ Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹⁵ Department of Radiology, Baylor College of Medicine, Houston, TX, USA.

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.

Keywords: Cancer; Immune response; Omics.

Grants and funding

P50 CA168504/CA/NCI NIH HHS/United States