CPTAC investigators from Baylor College of Medicine and the Broad Institute of MIT and Harvard in collaboration with oncologists at Washington University in St. Louis have identified biological markers in triple negative breast cancer (TNBC) that are associated with resistance to chemotherapy treatment. Their study, published in Cancer Discovery, deployed an innovative analytic approach called “microscaled proteogenomics” to probe the molecular basis for differential response to chemotherapy of TNBC patients. Data from standard DNA and RNA sequencing approaches were integrated with mass spectrometry-based proteomic and phosphoproteomic analyses to derive more complete molecular portraits of treatment-responsive versus treatment-resistant tumors.
“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 Dr. Meenakshi Anurag, assistant professor of medicine at the Lester and Sue Smith Breast Center at Baylor. “It is imperative that we develop approaches to predict response so that only effective treatments are given. Furthermore, patients who don’t respond to standard drugs need entirely new treatment approaches. The discovery of therapeutic alternatives will depend on new insights into how TNBC arises.”
The team conducted analyses that triangulated treatment response, chromosomal deletion or gain and concordant decreases or increases in mRNA and protein expression. This led the team to determine that a deletion on chromosome 19, located in a region called 19q13.31-33, was associated with resistance to chemotherapy treatment. Of the hundreds of genes deleted in this location, expression of the DNA ligase gene LIG1 was one of the mostly consistently suppressed genes at both the mRNA and protein level. 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 is a critical component of lagging strand DNA synthesis that connects Okazaki fragments (small DNA segments that must be connected to complete the DNA synthesis reaction). Interestingly, the lagging stand DNA polymerase POLD1 is frequently co-deleted with LIG1, suggesting a multigenic mechanism is in play. Lagging-strand synthesis components are generally considered essential to cellular survival. However, the team discovered that reductions in the levels of these enzymes were associated with marked chromosomal instability in multiple cancer types and selective carboplatin resistance in TNBC. Mechanistic studies are underway to determine how the genome is destabilized and how tumors with LIG1 deletion can be more effectively treated.
Dr. Matthew Ellis, a McNair Scholar at Baylor and director of the Lester and Sue Smith Breast Center at the time of this research, and Dr. Steve Carr, Senior Director of Proteomics 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.”
Investigators were funded within the NCI’s CPTAC as a multidisciplinary Proteogenomic Translational Research Center to apply proteomic and genomic approaches to clinically-relevant research projects that use clinical trial samples to understand drug response and therapeutic resistance.