Sotorasib combined with 3-methyladenine for the treatment of KRAS G12C-mutant pancreatic cancer and its underlying mechanisms.

Pancreatic cancer is a gastrointestinal malignancy with an insidious onset and rapid progression. Due to limited therapeutic strategies, its mortality remains high. The KRAS gene is among the most frequently mutated genes in solid tumors, and the development of drugs targeting KRAS mutations in pancreatic cancer is a current research focus. Sotorasib (AMG510) is the first small-molecule KRAS G12C-targeted inhibitor approved by the FDA for clinical use and has demonstrated safety and antitumor activity in tumors such as colorectal cancer and non-small cell lung cancer.

At present, studies on the mechanisms of AMG510 in KRAS G12C-mutant pancreatic cancer are still at an early stage.

This study aimed to investigate the effects of AMG510 on KRAS G12C-mutant pancreatic cancer cells and to preliminarily explore its mechanism of action. AMG510 inhibited the initiation and progression of KRAS G12C-mutant pancreatic cancer by inducing reactive oxygen species (ROS) accumulation, mitochondrial damage, cell cycle arrest, and apoptosis. RNA-seq revealed that AMG510 triggered cytoprotective autophagy in KRAS G12C-mutant pancreatic cancer. Treatment with the combination of AMG510 and the early autophagy inhibitor 3-methyladenine(3-MA) further suppressed proliferation and promoted apoptosis.

Mouse experiments confirmed the biosafety and efficacy of AMG510 combined with 3-MA in vivo.

The results of this study revealed that AMG510 exhibited favorable antitumor activity against KRAS G12C-mutant pancreatic cancer in vitro and in vivo, and the combination of AMG510 and 3-MA may represent a candidate therapeutic regimen for the clinical treatment of KRAS G12C-mutant pancreatic cancer.