CLAMPs allow single cell tracking of KRASG12C inhibition and endow druggability to KRAS mutants

Abstract The discovery of covalent inhibitors binding the switch II (SWII) pocket has enabled therapeutic intervention in KRASG12C driven tumors and represents a milestone in targeting KRAS-driven cancers. However, the transient nature and high energetic barrier required for binding this pocket has been an obstacle in successfully targeting other KRAS mutant oncoproteins. We report the discovery of KRAS Conformation Locking Antibodies for Molecular Probe discovery (CLAMP)s that specifically recognize the unique conformation of KRASG12C induced by covalent inhibitors. KRAS CLAMPs enable single cell resolution of covalent inhibitor-bound KRASG12C in cells and in vivo tumor models, providing a biomarker for direct target engagement of KRASG12C inhibition. KRAS CLAMPs bind multiple KRAS mutants and stabilize an open conformation of the SWII pocket increasing the affinity of weak non-covalent SWII pocket ligands. This work provides new insights into KRASG12C upon treatment with covalent inhibitors and offers a path towards targeting the SWII pocket in other RAS mutants.