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Tiejun Bing

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Jul 2026

Abstract A068: Multi-omics validated KRASi-resistant cell lines for combination and sequential drug treatment discovery

Despite the transformative efficacy of KRAS inhibitors in KRAS-mutant malignancies, intrinsic refractoriness and adaptive resistance markedly impair durable treatment responses. Preclinical models that recapitulate the molecular heterogeneity and evolutionary features of clinical resistance are therefore essential for rationally developing and validating combinatorial and sequential strategies to overcome KRAS inhibitor resistance. 1) Generation of KRAS inhibitor-resistant cell lines: More than 10 KRAS inhibitor-resistant cell lines were established through prolonged exposure of KRAS-mutant cancer cells to clinically approved KRAS inhibitors, as well as emerging agents. 2) Exploration of resistance mechanism: Integrated multi-omics analyses, including transcriptomic and proteomic profiling, were performed to delineate the molecular determinants of resistance and to predict candidate synergistic combination partners.3) High-throughput combination screening: More than 3000 drug combinations (including KRAS inhibitors, targeted agents against bypass pathways, DDR inhibitors, et al) were tested using a customized resistant cell panel to identify. 4) Mechanistic validation: Key signaling pathways (e.g., MAPK, PI3K-AKT, DDR) were interrogated via Western blot and phospho-protein arrays to confirm the functional relevance of predicted resistance mechanisms and combination efficacy. Multi-omic profiling of these resistant cell lines revealed diverse mechanisms of resistance, including activation of bypass pathways, KRAS isoform switching, and metabolic reprogramming. Using this well-characterized cell panel, we systematically screened combinatorial and sequential therapeutic strategies and identified multiple actionable regimens that restored cellular sensitivity to KRAS-targeted agents. Further in vivo therapeutic efficacy evaluation using xenograft models is currently ongoing to validate the translational potential of these lead regimens. We have established a fully characterized, multi-omic-profiled panel of KRAS inhibitor-resistant cell lines that provides a physiologically relevant and mechanistically annotated platform for discovering novel therapeutic strategies. This resource accelerates the evaluation of drug efficacy across diverse resistance contexts and KRAS mutation subtypes. The seamless integration of in vitro screening with ongoing in vivo model development creates a translational pipeline for advancing next-generation regimens aimed at overcoming KRAS inhibitor resistance Liuxian Meng, Ying Bi, Xinuo Zhang, Xuemei Jin, Guangyue Gong, Zhengtai Li, Tiejun Bing. Multi-omics validated KRASi-resistant cell lines for combination and sequential drug treatment discovery [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 A068.

Liuxian Meng, Yingxin Bi, Xinuo Zhang et al. · Clinical Cancer Research · 0 citations

Jul 2026

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.

Qing Xue, Zhuo Meng, Xuebing Yang et al. · Clinical Cancer Research · 0 citations