Anti-tumor activity of orally available cyclic peptide LUNA18 through direct pan-RAS inhibition across diverse RAS genetic alterations

Although recent extensive efforts led to the landmark discovery of clinically effective KRASG12C inhibitors (KRASG12C-i), targeting RAS genetic alterations beyond the G12C mutant remains challenging. Here we report on LUNA18 (paluratide), an orally available cyclic peptide that acts as a first-in-class pan-RAS GDP inhibitor, exhibiting potent inhibitory activity against a wide variety of RAS mutations. LUNA18 demonstrated anti-tumor effects against cancer cells with various RAS alterations, including G12 and G13 mutations as well as KRAS amplification. Moreover, LUNA18 showed synergistic anti-tumor effects when combined with agents targeting receptor tyrosine kinase (RTK) and the mitogen-activated protein kinase (MAPK) pathway. Notably, under long-term treatment and growth factor stimulation, LUNA18 induced more potent and sustained signal inhibition than KRASG12C-i. LUNA18 can sustain MAPK pathway suppression via RAS wild-type (RAS WT) inactivation, which produces this enhanced inhibitory effect in KRAS-mutant cancers where RAS WT acts as a critical regulator of MAPK signaling. In xenograft models where the efficacy of KRASG12C-i was limited, combination with LUNA18 achieved more durable anti-tumor effects compared with the monotherapies. These findings suggest that LUNA18 could be a promising new therapeutic option for RAS-driven cancers.