Biological and targeting differences between the rare KRAS A146T and canonical KRAS mutants in gastric cancer models

• DOI: 10.1007/s10120-024-01468-8
• Publication Date: 2024-01-23T16:02:30Z
• Authors: Elisabetta Puliga; Chiara De Bellis; Sandra Vietti Mic...; Tania Capeloa; Cristina Migliore; Claudia Orrù; Gian Luca Baiocchi; Giovanni De Manzoni; Filippo Pietrantonio; Rossella Reddavid; Uberto Fumagalli ...; Chiara Ambrogio; Simona Corso; Silvia Giordano
• Keywords: Trametinib

Abstract Background Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, with a poor prognosis for patients advanced disease. Since oncogenic role KRAS mutants has been poorly investigated in GC, this study aims to biochemically and biologically characterize different KRAS-mutated models unravel differences among response therapy. Methods Taking advantage proprietary, molecularly annotated platform more than 200 GC PDXs (patient-derived xenografts), we identified PDXs, from which primary cell lines were established. The challenged downstream inhibitors vitro vivo experiments. Results Cells expressing rare A146T mutant showed lower RAS-GTP levels compared those bearing canonical G12/13D mutations. Nevertheless, all cells displayed addiction. Surprisingly, even if GEF SOS1 considered critical activation mutants, its abrogation did not significantly affect viability. From pharmacologic point view, Trametinib monotherapy was effective G12D -mutated models, suggesting vulnerability MEK inhibition. However, presence mutations PI3K pathway, frequently co-occurrent association AKT inhibitor MK-2206 required optimize response. Conclusion A deeper genomic biological characterization might sustain development efficient long-lasting therapeutic options harbouring -driven GC.