Targeting RAS in Pediatric Cancer

Division Of Basic Sciences - Nci

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Abstract

Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Pre-clinical studies indicate these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit. We previously showed preclinical therapeutic synergy between a MEK inhibitor, trametinib, and a monoclonal antibody specific for IGF1R, ganitumab in RAS-mutated rhabdomyosarcoma. Neuroblastoma cells, like rhabdomyosarcoma cells, are sensitive to inhibition of the RAS/MAPK and IGF1R/AKT/mTOR pathways. We hypothesized that the com-bination of trametinib and ganitumab would be effective in RAS-mutated neuroblastoma. In this study, trametinib and ganitumab synergistically suppressed neuroblastoma cell proliferation and induced apoptosis in cell culture. We also observed a delay in tumor initiation and prolongation of survival in heterotopic and orthotopic xenograft models treated with trametinib and ganitumab. However, growth of both primary and metastatic tumors was observed in animals receiving the combination of trametinib and ganitumab. Therefore, more preclinical work is necessary before testing this combination in patients with relapsed or refractory RAS-mutated neuroblastoma. This work was recently published in Cancers. 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 K-, H-, or NRAS(G12C) have been observed, including rhabdomyosarcoma and neuroblastoma tumors. The efficacy of KRAS(G12C) inhibitors in pediatric malignancies is currently unknown, and the ability of these drugs to modify H- and NRAS(G12C) has not been completely characterized. Here, 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 H- and NRAS(G12C), but only sotorasib decreased ERK phosphorylation in cells expressing H- or NRAS(G12C). Importantly, sotorasib also decreased ERK phosphorylation in a NRAS(G12C)-altered cell line xenograft model. These results suggest that pediatric patients with N- or KRAS(G12C)-altered solid tumors may benefit from sotorasib treatment. This work is currently in resubmission at Molecular Cancer Therapeutics. In ongoing work, we are evaluating the efficacy of KRAS(G12D) inhibitors in pediatric cancer. We are also evaluating the efficacy of a combination of trametinib and istiratumab in pediatric cancer. Finally, we are investigating the impact of MEK inhibition on FN-RMS metastasis.