KRAS G 12C -inhibitor-based combination therapies for pancreatic cancer: insights from drug screening.

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto-oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRAS ^G12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRAS ^G12C -inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine-protein phosphatase non-receptor type 11 (PTPN11)/Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibitors, and broad-spectrum multi-kinase inhibitors. Validation in a novel and unique KRAS ^G12C -mutated patient-derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRAS ^G12C -inhibitor efficacy, guiding clinical trial design and molecular tumor boards.
(© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)