Researchers Identify Chemotherapy Resistance Biomarkers in Triple-Negative Breast Cancer

DNA and RNA sequencing could provide insight about resistance to chemotherapy in patients suffering from triple-negative breast cancer.

Biological markers in patients with triple-negative breast cancer (TNBC) may be associated with resistance to chemotherapy treatment, according to researchers at Baylor College of Medicine, the Broad Institute of MIT and Harvard, and clinicians at Washington University in St. Louis.

“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 Meenakshi Anurag, assistant professor of medicine at the Lester and Sue Smith Breast Center at Baylor, in a press release.

Knowing how to predict response to treatment can help clinicians provide only effective treatments, Anurag noted in the press release. This offers further insight on TNBC that could lead to the development of alternate therapies and treatment options.

Using an innovative analytical approach dubbed “microscaled proteogenomics,” the team produced a complete molecular portrait of treatment-responsive vs treatment-resistant tumors. This new process integrates data from standard DNA and RNA sequencing approaches with mass spectrometry-based proteomics and phosphoproteomic analyses. It was originally developed to analyze tumor biopsies from patients with TNBC before using combination carboplatin and docetaxel chemotherapy.

“The proteomic analysis of pretreatment biopsies uniquely revealed metabolic pathways that were associated with resistance to treatment, including fatty acid metabolism,” Anurag said in the press release.

Accordingly, the team noticed that a higher occurrence of DNA repair signatures signaled greater sensitivity to chemotherapy. Interferon gamma signaling and immune checkpoint components were additional biomarkers that signified when a patient experienced chemotherapy sensitivity.

Following their analysis, Anurag and team performed further analysis on genes and chromosomes. They determined that deleting chromosome 19 was associated with chemotherapy treatment resistance.

Although hundreds of genes were deleted in the chromosome 19 region, the LIG1 DNA ligase gene was most consistently suppressed—LIG1 is a component of lagging strand DNA synthesis that is important for cell survival. In this case, low LIG1 levels were associated with resistance to chemotherapy treatment in patients with TNBC.

“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,” the researchers said in the press release.

“In our view, proteogenomic analyses should be routine in clinical trials to discover clinically useful biomarkers, new biological insight and therapeutic hypotheses,” said Shankha Satpathy, co-corresponding author of the study and senior group leader at the Proteomics Platform at Broad, in the press release.

The study was published in Cancer Discovery and funded by the National Cancer Institute’s Clinical Proteomics Tumor Analysis Consortium.

Reference

Baylor College of Medicine. Researchers identified markers of chemotherapy resistance and outcome in triple negative breast cancer. EurekAlert! August 24, 2022. August 25, 2022. https://www.eurekalert.org/news-releases/962752