Abstract IA06: Title of the talk: KRAS - Degrading the Undruggable

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

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. 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.

Abstract B040: Hold-to-Kill: RIPTAC Expanding Induced Proximity from Target Engagement to Therapeutic Window

RIPTAC (Regulated Induced Proximity Targeting Chimeras) introduces a novel strategy that leverages induced proximity to achieve selective cancer cell killing. Using AR-BRD4 RIPTAC II-5 as a tool compound, we integrated biochemical screening, computational docking, and multi-level cellular and in vivo assays to establish a direct link between target engagement and therapeutic efficacy. Biochemical evaluation confirmed binary and ternary affinity, supported by computational simulations that predicted novel AR-BRD4 ternary protein-protein interactions (neoPPIs) consis-tent with cooperativity observed experimentally. II-5's distinct slow on/off binding kinetics stabilize ternary complexes, translating into superior ac-tivity in ternary formation and downstream signaling modulation. Cellular assays demonstrated that II-5 induces ternary complexes in HEK293T AR OE, VCaP, and LNCaP cells, correlating with strong inhibition of BRD4-driven signaling (c-Myc) while only moderately inhibit AR signaling (re-porter and PSA). In vivo CDX models further validated ternary complex formation, PSA reduction, and pharmacodynamic biomarker responses, showing that ternary assembly is preserved across biochemical, cellular, and tumor tissue contexts. II-5 was highly potent in AR-high prostate cancer models, with efficacy scaling across AR mutants and expression levels, highlighting a mechanistic correlation between AR expression and therapeutic effect. This enables RIPTAC to address resistance mechanisms such as AR amplification, point mutations, etc. Safety panel profiling indicates an overall favorable profile with limited off-target activity. Beyond AR-BRD4, RIPTAC expands the induced proximity landscape, aligning with TCIP paradigms and demonstrating broader applicability across oncogenic drivers. Together, computational and experimental evidence converge to highlight ternary complex stability and AR expression dependence as the mechanistic drivers of RIPTAC's therapeutic window. Importantly, our induced proximity platform, built on extensive expertise in targeted protein degradation (TPD), can be rapidly migrated to other target pairs, enabling first-in-class drug discovery programs and supporting both domestic and international partners. Qing Xue, Zhu Meng, Xue Yang, Tanfeng Zhao, Zhaoxia Yin, Lili Chai, Yanan Zhao, Qian Wang, Wei Liu, Tiejun Bing. Hold-to-Kill: RIPTAC Expanding Induced Proximity from Target Engagement to Therapeutic Window [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 B040.

Discovery of a Potent and Selective KRAS G12D Degrader based on PROTAC Degradation.

KRAS-G12D has long been regarded as an intractable therapeutic target due to the flat binding pocket and its strong affinity for GTP/GDP. Proteolysis-targeting chimera (PROTAC) is a revolutionary drug discovery strategy that, by virtue of its unique pharmacological mode of action, provides more options for targeting undruggable targets. In this study, we designed and synthesized 20 novel KRAS G12D PROTACs based on the MRTX1133 derivative. Through systematic exploration of linker structure-activity relationship and multi-cell line screening, compound VI-1 exhibited significant KRAS G12D degradation activity in PANC-0203 cells, achieving 69% effective degradation at 10 μM. Notably, the preferred compounds exhibited significant selectivity for other KRAS mutations and normal cells. This work provides an important lead compound for developing highly selective KRAS G12D PROTACs and warrants further exploration in the context of drug-likeness optimization.

Evolution of KRAS molecular glues: from allele-selective to Pan-RAS and protein-protein interaction modulators.

Abstract B045: Targeted degradation of cyclin T1 constrains transcription elongation and triggers tumour cell apoptosis

Transcriptional dysregulation is a hallmark of cancer and is frequently driven by oncogenic alterations that rewire downstream gene-expression programmes. Although kinase inhibitors targeting upstream oncogenic drivers can produce clinical benefit, responses are often limited by acquired resistance and pathway adaptation. Targeting transcriptional dependencies therefore represents an alternative therapeutic strategy. The positive transcription elongation factor b complex, composed of CDK9 and Cyclin T1(CCNT1), is a central regulator of RNA polymerase II transcriptional elongation and supports the expression of genes required for tumour cell survival. However, conventional CDK9 inhibitors often lack sufficient selectivity and are associated with dose-limiting toxicities. Here, we report the rational design of a novel CCNT1-targeting binder and its application in biological proteolysis-targeting chimeras designed to selectively degrade Cyclin T1. The degrader platform combines E3 ubiquitin ligase recruitment with a dual-peptide CCNT1-binding module derived from the pTEFb-interacting partners AFF4 and HIV-TAT. This engineered recruitment strategy enabled robust and selective depletion of both tagged and endogenous CCNT1 in cancer cells. CCNT1 degradation was accompanied by destabilisation of its catalytic partner CDK9 and reduced phosphorylation of RNA polymerase II, consistent with suppression of transcriptional elongation. Functionally, CCNT1-targeted degradation produced marked anti-tumour effects in lung cancer models. Degrader-treated cells showed impaired proliferative capacity, reduced colony formation, cell-cycle disruption across multiple checkpoints, and induction of apoptosis. These findings demonstrate that selective degradation of CCNT1 can effectively collapse pTEFb-dependent transcriptional programmes and compromise tumour cell fitness. Together, our study establishes a novel CCNT1 binder-enabled degrader strategy as a translational approach to targeting transcriptional addiction in cancer. By moving beyond catalytic CDK9 inhibition and directly eliminating the Cyclin T1 scaffold, CCNT1-targeted degradation may offer a more selective and durable route for therapeutic intervention in transcriptionally dependent tumours. Janice Wenzheng Neng, Laura Blenkarn, Laura S. Itzhaki, Catherine H. Wilson. Targeted degradation of cyclin T1 constrains transcription elongation and triggers tumour cell apoptosis [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 B045.

KRAS G12C-Targeted Therapy Strategy for Lung Cancer: Mechanism, Clinical Practice and Challenges

This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision-making and further research in this field.