The team used an innovative analytical method called “microprotein molecules” that they had previously developed (Satpathy et al., 2020) to analyze tumor biopsies taken from TNBC patients. prior to treatment with the combination chemotherapy of carboplatin and docetaxel. Data from standard DNA and RNA sequencing methods were integrated with mass spectrometry-based proteomics and phosphoproteomic analyzes to obtain a more complete molecular portrait of treatment-responsive vs. treatment.
Anurag, also a member of Baylor’s Dan L Duncan Comprehensive Cancer Center, said: “Protein analysis in pretreatment biopsies has uniquely revealed the metabolic pathways involved in resistance to resistance. treatment, including fatty acid metabolism. When the team looked at both gene and protein expression data together, they observed that chemosensitivity was marked by higher DNA repair markers, interferon gamma signaling, and score components. immune test. These data suggest that a multimodal predictor for chemotherapy response is within reach.
The team then analyzed that the triangulation treatment response, chromosomal deletion or gain, and decreased or increased mRNA and protein expression were concurrent. 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. Among the hundreds of genes deleted at this location, the expression of the DNA ligase gene LIG1 is one of the most frequently suppressed at both the mRNA and protein levels. In model systems and in other TNBC data sets, loss of LIG1 expression and/or knockout has been associated with selective carboplatin resistance and poor clinical outcomes.
Dr. Matthew Ellis, a McNair Scholar at Baylor and director of the Lester and Sue Smith Breast Center at the time of this study, and Dr. Steve Carr, senior director of the Proteomics Foundation and an institute scientist at Broad, who jointly orchestrated the analysis, said, “This groundbreaking study clearly demonstrates the power of combining microproteomic analyzes with careful clinical research to generate insights. new to the nature of cancer.”
LIG1 is an important component of late-stranded DNA synthesis, connecting Okazaki fragments (small pieces of DNA that must be connected to complete fusion). Interestingly, the lagging scaffold DNA polymerase POLD1 is often co-deleted with LIG1, suggesting an active pluripotency mechanism. Late-chain synthesis components are generally considered essential for cell survival, but here reduced levels of these enzymes have been implicated in chromosomal instability in many cancers and selective resistance to carboplatin in TNBC. Mechanistic studies are underway to determine how the genome is destabilized and how LIG1-deleted tumors can be treated more effectively.