Journal Article

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

Capeloa, Tania, Reddavid, Rossella, Migliore, Cristina, Vietti Michelina, Sandra, Corso, Simona, Fumagalli Romario, Uberto, Puliga, Elisabetta, De Manzoni, Giovanni, De Bellis, Chiara, Pietrantonio, Filippo, Orrù, Claudia, Giordano, Silvia, Ambrogio, Chiara, Baiocchi, Gian Luca

2024

Overview

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

• Publisher: Springer Nature Singapore,Springer Nature B.V
• Subject: 1-Phosphatidylinositol 3-kinase / Abdominal Surgery / Addictions / AKT protein / Cancer Research / Cell growth / Cell Line, Tumor / Cell viability / Experiments / Gastric cancer / Gastroenterology / Gene expression / Humans / K-Ras protein / Laboratory animals / Medical prognosis / Medicine / Medicine & Public Health / Mutants / Mutation / Oncology / Original / Original Article / Pancreatic cancer / Phosphatidylinositol 3-Kinases - metabolism / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins p21(ras) - genetics / Stomach Neoplasms - drug therapy / Stomach Neoplasms - genetics / Surgical Oncology / Tumors