Activity of Direct KRAS(G12C) Inhibitors in Preclinical Models of Pediatric Cancer.

Abstract

Directly targeting RAS is a promising approach for the treatment of RAS-altered malignancies. Recently, several groups have developed mutation-specific agents such as sotorasib and adagrasib, which directly target KRAS by covalently modifying KRAS(G12C). KRAS is commonly altered in adult malignancies, such as lung, pancreatic, and colorectal adenocarcinomas, but is less commonly altered in pediatric cancers. However, rare pediatric solid tumors harboring KRAS(G12C), HRAS(G12C), or NRAS(G12C) have been observed, including rhabdomyosarcoma and neuroblastoma tumors, as well as leukemias. The efficacy of KRAS(G12C) inhibitors in pediatric malignancies is currently unknown, and the ability of these drugs to modify HRAS(G12C) and NRAS(G12C) has not been completely characterized. In this study, we show that sotorasib, adagrasib, and the RAS-ON inhibitor RMC-6291 are effective in a neuroblastoma cell line altered by KRAS(G12C). We further demonstrated that sotorasib and adagrasib inhibited SOS-mediated guanine nucleotide exchange on HRAS(G12C) and NRAS(G12C). Sotorasib and RMC-6291 decreased ERK phosphorylation in cells expressing HRAS(G12C), KRAS(G12C), or NRAS(G12C). Importantly, sotorasib also decreased ERK phosphorylation in a NRAS(G12C)-altered cell line xenograft model; however, this treatment did not prolong survival as a single agent. These results suggest that combinations of targeted agents that include sotorasib may be required for clinical benefit in pediatric patients with HRAS(G12C)- or NRAS(G12C)-altered malignancies, in addition to those with KRAS(G12C)-altered malignancies.