Abstract IA05: Eliminating the oncogenic driver: Advancing targeted degradation of KRAS

Abstract Alterations in KRAS are among the most common oncogenic drivers in solid tumors, including pancreatic, colorectal, and lung cancers, with G12D, G12V, and G12C representing the most frequent mutations. Unlike wild-type KRAS, which cycles between inactive and active states, mutant KRAS is constitutively active and drives uncontrolled proliferation and survival through downstream signaling. KRAS PROteolysis TArgeting Chimera (PROTAC) degraders are designed to eliminate the oncogenic protein, thereby stopping this dysregulated signaling cascade at the source. Their iterative mechanism, in which one PROTAC molecule can degrade multiple target proteins, may offer advantages over inhibitors, particularly in tumors with KRAS amplification, a common feature of KRAS-driven cancers and a resistance mechanism to inhibitor therapy. KRAS degradation may also produce deeper, more sustained pathway suppression and a distinct resistance profile compared with inhibition. Both mutation-selective and pan-KRAS PROTAC degraders have been identified and will be described herein. Both classes of PROTAC degraders target the ON and OFF forms of KRAS while sparing the related isoforms, HRAS and NRAS. ARV-806 is a PROTAC KRAS G12D-selective degrader currently being evaluated in a Phase1/2 clinical study (NCT07023731). Preclinically, ARV-806 demonstrated sub-nanomolar potency for degrading KRAS G12D and >25-fold greater anti-proliferative potency compared to inhibitors and another clinical-stage degrader. In vivo, ARV-806 induced robust KRAS G12D degradation that was sustained for >7 days after a single IV dose and produced tumor regressions across multiple models. Orally bioavailable PROTAC pan-KRAS degraders have also been identified that potently degrade common KRAS mutations like G12C/D/V, difficult-to-target variants such as G12R and Q61H, and amplified KRAS. In vitro, degradation led to potent antiproliferative activity and induction of apoptosis of KRAS-driven cells, with no observed impact on cells not driven by KRAS. In vivo, treatment with the PROTAC pan-KRAS degrader led to regressions in multiple tumor models bearing different KRAS mutations. Additionally, a sustained pharmacodynamic effect was observed with the PROTAC pan-KRAS degrader inducing prolonged suppression of KRAS protein levels and downstream signaling compared to an inhibitor. In a KRAS-mutant syngeneic model, pan-KRAS degradation combined with immune checkpoint inhibition produced more complete responses than a pan-RAS inhibitor combination, accompanied by increased cytotoxic T-cell and dendritic-cell infiltration, reduced myeloid populations, and enhanced immune checkpoint response gene signatures. Together, these findings support oral pan-KRAS degraders as a differentiated therapeutic approach for KRAS-driven cancers, with potential advantages in monotherapy activity, durability, immune engagement, and tolerability relative to pan-RAS targeting. Citation Format: Kathryn D. Smith. Eliminating the oncogenic driver: Advancing targeted degradation of KRAS [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr IA05.