RAS-ON vs RAS-OFF inhibitors in PDAC: Exploring Daraxonrasib

Recent advances in targeting RAS mutations in pancreatic cancer are showing promising results. RAS proteins exist in 2 states: an inactive GDP-bound form (RAS-OFF) and an active GTP-bound form (RAS-ON). When RAS is in its active state, it continuously signals cells to grow and divide, driving cancer progression. This active form is tightly bound and historically difficult to inhibit because it behaves like a switch that is stuck in the “on” position, relentlessly promoting tumor growth. Most traditional RAS inhibitors have targeted the inactive, GDP-bound state, but this approach has limitations in effectively controlling cancer driven by RAS mutations.

New therapeutic agents are now able to target the active, GTP-bound RAS state directly, effectively shutting down the continuous growth signals. This represents a significant breakthrough, as these inhibitors can lock RAS in an inactive form even when it is stuck in the active state. Early clinical trials of these RAS-ON inhibitors have demonstrated encouraging responses, especially in pancreatic cancer patients with RAS mutations. The ability to inhibit the active form of RAS offers a novel mechanism to halt tumor progression and presents new hope for a cancer type that has traditionally been difficult to treat.

One such inhibitor has been evaluated in phase 1 studies involving patients with refractory pancreatic cancer. Results showed a response rate of approximately 25% to 29%, which is notably higher than typical second-line treatment responses in this setting. Additionally, patients exhibited declines in circulating tumor DNA and experienced progression-free survival of 8 to 9 months. While these early trials are small and nonrandomized, the data support further development and larger studies. This new class of RAS-ON inhibitors could potentially transform the therapeutic landscape for pancreatic cancer, offering more effective targeted treatment options in the near future.