Neoadjuvant chemotherapy (NAC) is the standard of care for many triple-negative breast cancer (TNBC patients), who lack estrogen and progesterone receptors as well as the HER2 receptor. Although NAC is effective in some TNBC patients, approximately half will develop chemotherapy resistance. Researchers are working to develop and improve approaches that overcome resistance to chemotherapy. Now, researchers at Baylor College of Medicine and the Broad Institute of MIT and Harvard, and clinicians at Washington University in St. Louis have identified biological markers in TNBC that are associated with resistance to chemotherapy treatment.

Their findings are published in Cancer Discovery in a paper titled, “Proteogenomic markers of chemotherapy resistance and response in triple-negative breast cancer.”

“Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for TNBC,” wrote the researchers.

“TNBC is the most difficult to treat form of breast cancer, with standard treatment requiring multiple chemotherapy drugs that unfortunately often fail to cure the patient,” said first and co-corresponding author Meenakshi Anurag, PhD, assistant professor of medicine at the Lester and Sue Smith Breast Center at Baylor.

The research team used an innovative analytic approach called “microscaled proteogenomics” that they previously developed. They integrated data from standard DNA and RNA sequencing approaches with mass spectrometry-based proteomics and phosphoproteomic analyses to derive more complete molecular portraits of treatment-responsive versus treatment-resistant tumors.

“The proteomic analysis of pretreatment biopsies uniquely revealed metabolic pathways that were associated with resistance to treatment, including fatty acid metabolism,” said Anurag. When the team considered both proteomics and gene expression data together, they observed that sensitivity to chemotherapy was marked by higher DNA repair signatures, interferon gamma signaling, and immune checkpoint components. These data suggest a multi-omics predictor for chemotherapy response is within reach.

The team then conducted analyses that triangulated treatment response, chromosomal deletion or gain, and concordant decreases or increases in mRNA and protein expression. The DNA ligase gene LIG1 was one of the most consistently suppressed genes at both the mRNA and protein levels. In model systems, and in other TNBC data sets, loss of expression and/or deletion of LIG1 was associated with selective carboplatin resistance and poor clinical outcome.

“LIG1 loss was also associated with poor prognosis in other cancer types, showing that this deletion has broader clinical significance,” Anurag said. The researchers are currently working on clinical grade assays to confirm that LIG1 loss can be safely used to direct carboplatin chemotherapy in TNBC.

Matthew Ellis, PhD, a McNair Scholar at Baylor and director of the Lester and Sue Smith Breast Center at the time of this research, and Steve Carr, PhD, senior director of the Proteomics Platform and an institute scientist at Broad, who together orchestrated the analysis, said, “This groundbreaking study clearly reveals the power of combining microscaled proteogenomic analyses with careful clinical research to produce new insights into the nature of cancer.”

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