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Approximately 30% of all cancers have mutations in the KRAS proto-oncogene, GTPase (KRAS), and approximately 88% of pancreatic cancer tumors have mutations in KRAS. Recently, a novel KRAS inhibitor, daraxonrasib, with activity against both wild-type and mutant KRAS, has been developed and has shown efficacy in a phase III clinical trial of recurrent pancreatic-cancer patients, but with significant side-effects. In the present report, we determined whether daraxonrasib is synergistic with recombinant methioninase (rMETase) on pancreatic cancer cells that have the KRAS G12D mutation, compared to normal fibroblasts.

Cell viability was measured with the WST-8 reagent. The half-maximal inhibitory concentrations (IC₅₀) of rMETase and daraxonrasib were determined on PANC-1 human pancreatic cancer cells and Hs-27 human normal fibroblasts in vitro. The viability of PANC-1 and Hs-27 cells treated with rMETase alone, DXR alone, or a combination of rMETase and daraxonrasib was determined at their respective IC₅₀ values.

The IC₅₀ values of daraxonrasib were 10.5 μM for PANC-1 and 8.4 μM for Hs-27. The IC₅₀ values of rMETase were 0.47 U/ml for PANC-1 and 0.42 U/ml for Hs-27. Daraxonrasib alone and rMETase alone showed significantly higher cytotoxicity towards PANC-1 cancer cells than Hs-27 fibroblasts. The combination of daraxonrasib and rMETase demonstrated selective synergistic cytotoxicity toward PANC-1 cells compared to normal Hs-27 fibroblasts (p<0.05).

The present results suggest that the combination of daraxonrasib and rMETase has clinical potential for lowering the effective dose of daraxonrasib, thereby reducing daraxonrasib-associated side-effects, as well as increasing its efficacy.