Synergy of KRAS-inhibitor Daraxonrasib Combined With Recombinant Methioninase on Pancreatic-cancer Cells But Not Normal Cells.

BACKGROUND/AIM: 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.

MATERIALS AND METHODS: 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.

RESULTS: 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).

CONCLUSION: 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.