使用RAS抑制剂联合AMG 193(一种MTA协同的PRMT5抑制剂)靶向MTAP缺失/KRAS突变癌症

AMG 193 is a clinical stage MTA-cooperative PRMT5 inhibitor designed to exploit the metabolic vulnerability created by homozygous MTAP deletion in tumors. By binding PRMT5 in the presence of accumulated methylthioadenosine (MTA), AMG 193 selectively inhibits PRMT5 activity in MTAP-deleted cells resulting in alternative RNA splicing, DNA damage, and cell cycle arrest. In patients, AMG 193 has demonstrated single-agent antitumor activity and a favorable tolerability profile, supporting its potential as a precision therapy for MTAP-deleted cancers (Rodon et al, 2024). To further understand the potential for AMG 193 activity, we evaluated combination strategies using AMG 193. We previously demonstrated that AMG 193 synergizes with standard of care chemotherapy by increasing DNA damage, a strategy currently under clinical investigation (NCT06360354, NCT06333951). Given that MTAP deletions frequently co-occur with KRAS mutations in pancreatic ductal adenocarcinomas (PDAC; ~30%) and non-small cell lung cancer (NSCLC; ~4%), we hypothesized that dual inhibition of PRMT5 and RAS signaling could further enhance antitumor activity. Here, AMG 193 was evaluated in combination with the KRAS G12C inhibitor sotorasib or the pan-RAS inhibitor RMC-6236 (daraxonrasib). In the KRAS G12C mutant PDAC cell line MIAPACA2, all RAS inhibitor combinations exhibited similar levels of synergy (Combination Index < 0.5). Nuclear counts confirmed a greater cell growth inhibition in the combination groups and immunoblots confirmed inhibition of both PRMT5 and RAS signaling. RNA-seq analysis revealed synergistic regulation of the RAS pathway and an inhibition of translation and rRNA processing after sotorasib combination treatment. In vivo , combination treatment of AMG 193 with sotorasib in MIAPACA2 PDAC xenografts resulted in 28% tumor regression. In addition, AMG 193 combined with RMC-6236 produced robust synergy across a variety of KRAS G12X mutant PDAC and NSCLC cell lines in vitro . In vivo efficacy studies evaluating AMG 193 in combination with RAS inhibitors is ongoing in a variety of MTAP-deleted/KRAS mutant tumor models. We also observed that AMG 193 monotherapy efficacy was independent of KRAS mutational status in a NSCLC PDX mouse clinical trial. Overall, AMG 193 displays synergy with RAS targeted agents in vitro , and combination treatment with sotorasib in vivo substantially inhibits tumor growth. A clinical study evaluating AMG 193 in combination with RMC-6236 in MTAP-deleted PDAC is ongoing (NCT06360354).