Resistance and cancer progression remain a major obstacle to the successful treatment of cancer. In HER2-positive breast cancer, the development of targeted therapies, such as trastuzumab, has revolutionized the treatment for these cancer patients. However, a significant number of patients develop resistance. Therefore, understanding the causes of resistance is key for the development of better treatments. Multiple mechanisms contributing to the resistance to trastuzumab have been described. However, an important aspect of cancer cells has been largely overlooked: the aberrant glycosylation of cancer cells and how that could impact the efficacy of targeted therapies.
Therefore, the goal of this project was to provide a new focus to the challenge of resistance by deciphering the impact of glycosylation on resistance to HER2-targeted therapies. Aberrant glycosylation of proteins, including acquisition of unconventional N-glycosylation sites, is a hallmark in cancer and has been linked to multiple processes such as invasion of other tissues by tumor cells, tumor-induced angiogenesis, and immune response modulation. The receptor HER2, the main driver of HER2-positive breast cancers, is heavily glycosylated and is also the target of current antibody-based treatments, including trastuzumab. In this context, this project addressed (1) the identification of glycosylation-related genes associated with resistance to trastuzumab in patients to (2) dissect their role on trastuzumab binding and (3) assess their impact in the response to trastuzumab mediated by immune cells. This research has combined the analysis of clinical data from tumor biopsies with the use of trastuzumab-resistant tumor-derived breast cancer cell lines and implementation and imaging of 3D heterotypic cultures of cancer cell line-derived spheroids that also contain immune cells. Altogether, this project addressed a largely unexplored layer of complexity in cancer biology and, holds the potential to identify new markers of response to therapies and open the path to new therapeutic options for the improvement of current treatments.
