Transcriptional Reinforcement of the HER2-RAS Network in HER2-Positive Gastric Cancer: The RUNX-SOS1 Axis in Context.

HER2-positive gastric cancer represents a distinct molecular subtype characterized by chromosomal instability, variable HER2 amplification, and substantial intratumoral heterogeneity. Although HER2-targeted therapies have improved clinical outcomes, therapeutic resistance commonly develops and limits long-term benefit. Established resistance mechanisms include bypass signaling through alternative receptor tyrosine kinases, reactivation of downstream pathways such as PI3K-AKT and MAPK, and dynamic changes in HER2 expression during treatment. These findings underscore the complexity of signaling regulation in HER2-driven tumors and indicate that mechanisms beyond receptor-level inhibition contribute to persistent oncogenic signaling. In this review, we examine the concept of transcriptional reinforcement within the HER2-RAS signaling network and discuss RUNX-dependent regulation of SOS1 as a downstream mechanism that may sustain signaling activity. We position this regulatory axis within the broader landscape of established resistance mechanisms and emerging therapeutic strategies, including antibody-drug conjugates, kinase inhibitors, and rational combination approaches. By integrating canonical resistance pathways with transcriptional regulation, this review provides a balanced perspective on how downstream regulatory processes may influence therapeutic response in HER2-positive gastric cancer.