Adaptive resistance to SHP2-based vertical RAS-pathway inhibition in pancreatic cancer involves multifaceted routes towards dedifferentiation

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) critically depends on oncogenic KRAS signaling. The Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity. Allosteric SHP2 inhibition in vertical combination with mitogen-activated protein kinase (MAPK) or RAS inhibition demonstrates synergistic efficacy, delays the onset of resistance, and is currently being evaluated in clinical trials. Methods Employing a comprehensive set of models, including endogenous murine tumors, murine and human cell lines, and patient-derived organoids representing the full spectrum of PDAC molecular subtypes, we here explore the characteristics and mechanisms of adaptive resistance to dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) and dual SHP2/KRAS G12D inhibition. Results We observe potent anti-tumor efficacy of SHP2-based vertical RAS-pathway inhibition across all molecular PDAC subtypes. However, resistance eventually emerges and is commonly associated with tumor cell dedifferentiation. This dedifferentiation is marked by features of epithelial-to-mesenchymal transition (EMT), a shift in transcriptional molecular PDAC subtype, and cancer cell state transitions. Resistance involves increased RAS expression and/or context-dependent activation of various compensatory signaling pathways, including PI3K-AKT, JAK-STAT, or Wnt/β-catenin, Hippo, Rap1 and TGFβ. Conclusion These findings suggest that resistance to SHP2-based vertical RAS-pathway inhibition follows converging, yet molecularly heterogeneous, compensatory signaling trajectories. Consequently, precision medicine approaches that target specific signaling alterations or exploit the vulnerabilities of dedifferentiated cell states are necessary to overcome resistance and reinforce vertical RAS-pathway inhibition for effective pancreatic ductal adenocarcinoma (PDAC) treatment.