A new opportunity for an old target: HER2, glycosylation and ADCs
Ana Ruiz Saenz
CICbioGUNE, Derio, Vizcaya
Despite outstanding advances in cancer research, resistance to therapies remains a hurdle in the successful treatment of cancer. Interestingly, resistance is associated with a fitness cost: the rise of new vulnerabilities. These vulnerabilities represent new therapeutic opportunities and therefore, understanding the causes of resistance is key for the development of better treatments. In the case of HER2-amplified breast cancers, resistance to HER2-targeting agents undermines the efficacy of current treatments in a significant number of patients. Addressing the molecular mechanisms involved in resistance, we identified a novel strategy to target the undruggable HER3, the key partner of HER2 in HER2- amplified cancers. Our work also revealed the potential of HER2 to overcome HER3 requirement for tumor development and, functional-structural studies highlighted the resilience of HER2-HER3 dimers to sustain tumorigenic signaling. In a collaborative effort with other groups and using a high-throughput kinase activity platform recently developed, we identified a SRC-relayed inflammatory program as a driver of resistance in BRAFV600E colorectal cancers. Targeting this new pathway improves tumor growth inhibition in PDX models restoring therapeutic response to current treatments. Our most current research focuses on aberrant glycosylation, a hallmark of cancer linked to processes such as metastasis or modulation of the immune response. Yet, the impact of aberrant glycosylation on the efficacy of HER2-targeting therapies remains unknown. Therefore, integrating clinical data, mouse models, 3D co-culture immune-cancer systems and high-content live-imaging, we are currently deciphering the impact of altered glycosylation on the response to HER2- targeting agents, including the recent and promising antibody-drug conjugate, trastuzumab
deruxtecan.