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Although HER2\u2010targeted therapies have improved clinical outcomes, therapeutic resistance commonly develops and limits long\u2010term benefit. Established resistance mechanisms include bypass signaling through alternative receptor tyrosine kinases, reactivation of downstream pathways such as PI3K\u2013AKT and MAPK, and dynamic changes in HER2 expression during treatment. These findings underscore the complexity of signaling regulation in HER2\u2010driven tumors and indicate that mechanisms beyond receptor\u2010level inhibition contribute to persistent oncogenic signaling. In this review, we examine the concept of transcriptional reinforcement within the HER2\u2013RAS signaling network and discuss RUNX\u2010dependent 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\u2013drug 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\u2010positive gastric cancer.<\/jats:p>","DOI":"10.1111\/cas.70364","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T04:59:21Z","timestamp":1773809961000},"page":"1235-1243","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptional Reinforcement of the\n                    <scp>HER2<\/scp>\n                    \u2013\n                    <scp>RAS<\/scp>\n                    Network in\n                    <scp>HER2<\/scp>\n                    \u2010Positive Gastric Cancer: The\n                    <scp>RUNX<\/scp>\n                    \u2013\n                    <scp>SOS1<\/scp>\n                    Axis in 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