Preclinical Rationale for Targeting SHP2 with GH21 in MAPK-Active esophageal cancer and Combinatorial Regimens

Receptor tyrosine kinase (RTK)/MAPK pathway dysregulation drives malignant progression and therapeutic resistance in esophageal squamous cell carcinoma (ESCC). However, EGFR-targeted therapies have not yet been approved for ESCC and are frequently limited by acquired resistance. Here, we evaluated GH21, a potent SHP2 inhibitor that blocks a central signaling hub integrating inputs from multiple RTKs to the MAPK cascade. GH21 exerted robust antitumor effects and outperformed other tyrosine kinase inhibitors (TKIs). Proteomic profiling identified MAPK pathway activation as a defining feature of GH21-sensitive ESCC patient-derived organoids (PDOs), suggesting its potential as a predictive biomarker. Mechanistically, AURKB inhibition synergized with GH21 to overcome resistance through enhanced suppression of MAPK signaling. Furthermore, combining GH21 with immunotherapy remodeled the tumor microenvironment by activating immune cells, thereby potentiating antitumor immunity. Collectively, this study validates the therapeutic potential of GH21 in ESCC, proposes MAPK pathway activation as a potential candidate biomarker for patient selection, and provides a mechanistic rationale for GH21-based combination strategies, which are currently being evaluated in clinical trials (NCT06322095, NCT05183243).