The approval of KRASG12C selective inhibitors, sotorasib and adagrasib, marked a critical point in the effort to treat KRASG12C mutant NSCLC. Despite the initial clinical benefit observed after treatment, acquired resistance is observed in most patients representing an unmet medical need. Eukaryotic translation initiation factor 4E (eIF4E), a critical regulatory node for multiple oncogenic signaling pathways downstream of KRAS, including MAPK and PI3K pathways, is a promising target to overcome resistance to KRASmut targeted therapies.
Here, we present the development of a potent and selective eIF4E inhibitor, RBX-6610, for use in both KRASG12C targeted treatment-naïve and resistance settings. RBX-6610 elicits a reversible, dose-dependent cell cycle arrest and demonstrates consistent anti-proliferative effects in sotorasib/adagrasib-naïve and resistant cells. Furthermore, while RBX-6610 monotherapy in vivo causes significant tumor growth inhibition, the combination therapy with sotorasib results in significant tumor regression in both a naïve and treatment resistant setting. Collectively, these data support the addition of RBX-6610 to standard of care in KRASmut NSCLC patients. IND-enabling studies are planned, marking a significant step toward advancing RBX-6610, a potent eIF4E inhibitor, into the clinic.