Abstract KRAS is the most frequently mutated oncogene in cancer and a major driver of multiple malignancies. Currently, no approved therapies exist for patients with KRAS-mutated tumors beyond the KRAS G12C inhibitors, and the most clinically advanced agents target HRAS and NRAS in addition to KRAS. PROteolysis TArgeting Chimera (PROTAC) pan-KRAS degraders may offer advantages over traditional small-molecule inhibitors, including selectively targeting KRAS, which may allow for an improved therapeutic window while maintaining efficacy. Furthermore, PROTAC pan-KRAS degraders have iterative activity that may overcome the compensatory KRAS upregulation often observed after inhibitor treatment. We identified a potent and selective PROTAC pan-KRAS degrader that selectively targets KRAS while sparing HRAS and NRAS. This PROTAC forms a potent trimer complex with KRAS (both active and inactive forms) and an E3 ubiquitin ligase, which induces the ubiquitination and subsequent proteasomal degradation of KRAS. In mutant KRAS (mKRAS) cell lines, our PROTAC pan-KRAS degrader induced potent and selective degradation across a broad set of KRAS alterations, including G12C/D/V/S/R, G13D, Q61H, and wild-type (WT) amplified. The PROTAC induced similar maximal degradation in a non-amplified WT model and a KRAS WT-amplified model expressing ∼30-fold more KRAS protein (95% vs 90%), highlighting the benefit of iterative activity. Degradation of KRAS led to potent inhibition of mitogen-activated protein kinase (MAPK) pathway, apoptosis induction, and antiproliferative effects in spheroid models. Oral administration in xenograft models of pancreatic, lung, and colorectal cancer (CRC) models harboring mKRAS G12C/D/V or G13D resulted in robust tumor regressions, accompanied by KRAS degradation and MAPK pathway suppression. Additionally, in the CT26 syngeneic model (CRC) the PROTAC displayed substantial mKRAS degradation, MAPK pathway inhibition, and single-agent activity. Compared with a clinical pan-KRAS inhibitor or pan-RAS (ON) inhibitor, the PROTAC pan-KRAS degrader induced superior apoptosis induction and antiproliferative effects in WT-amplified and KRAS G13D spheroid models and had comparable activity in additional mKRAS models. Consistent with this result, the PROTAC induced greater tumor growth inhibition than the pan-RAS (ON) inhibitor (98% vs 82%) in a KRAS G13D xenograft model of CRC. Additionally, PROTAC-mediated degradation demonstrated differentiated protein modulation compared with inhibition as measured by proteomic analysis of 3 mKRAS spheroid models. Furthermore, in the CT26 syngeneic model, PROTAC treatment resulted in a higher rate of complete responses and prolonged survival compared with a clinical pan-RAS ON inhibitor and displayed strong synergy with immune checkpoint blockade, resulting in antitumor immunological memory. Together, these findings suggest that PROTAC KRAS-selective degraders have efficacy against tumors harboring multiple KRAS mutations and display differentiated activity compared with clinical pan-RAS (ON) or pan-KRAS inhibitors. Citation Format: Andrea Lopez-Arroyo, Jason M. Berk, Dana M. Klug, John P. Caldwell, Peter Hegan, Samantha Andella, Jessica Kraus, Amanda Chapman, Jennifer Pizzano, Mark Bookbinder, Debbie Gordon, Kim Davenport, Gregory Cadelina, Madeline A. Dorso, Emma Rousseau, Christopher Kuhlberg, Morena Scopel, Rebecca Conrad, William L. Corwin, Goutham Pattabiraman, Wendy Wu, Raushan Wilson, Christine Jones, John Corradi, Keith R. Hornberger, Angela M. Cacace, Ignacio J. Juncadella, Kathryn D. Smith. Preclinical activity of an orally bioavailable PROTAC pan-KRAS degrader versus inhibitors in mutant KRAS models abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr PR008.
Lopez-Arroyo et al. (Thu,) studied this question.