Role of MYC inhibition in overcoming resistance to HER2-targeted therapies for breast cancer

HER2-positive breast cancer is a distinct subtype of breast cancer defined by the overexpression of the human epithelial growth factor receptor 2 (HER2). HER2 promotes aggressive tumor growth and shows poor prognosis. HER2-targeted therapies, like trastuzumab and pertuzumab, have sufficiently improved patient outcomes, but eventually, most patients face resistance to HER2 therapies, resulting in ineffective clinical action. Recent knowledge has pointed to the oncogene MYC (as gene) as a major contributor to intrinsic and acquired resistance toward HER2-targeted therapies. Myc (as protein) overexpression promotes cell proliferation, survival, and metabolism reprogramming, permitting an escape from HER2 inhibition. Furthermore, Myc activation induces cellular reprogramming and activates downstream signalling pathways, including PI3K/AKT/mTOR and MAPK, which collectively contribute to resistance against HER2-targeted therapies. This review assesses the mechanistic role MYC plays in HER2-positive breast cancer progression and resistance, emphasizing preclinical studies that highlight the ability of Myc inhibition to restore sensitivity to HER2-directed therapeutics. Additionally, MYC targeting through small molecules, siRNA, or to enhance the delivery using nanoformulations, is a rapidly evolving strategy that may overcome resistance in the HER2-positive clinical context and improve therapeutic response. Furthermore, targeting Myc represents a logical and natural strategy to combine with HER2 therapies currently in use, and could potentially be a pivotal step forward in the development of effective combinatorial therapies. This review emphasizes the necessity of incorporating Myc-targeted strategies to address resistance and improve the durability of HER2-targeted therapy in breast cancer.