LBPO.ET03 · 实验与分子治疗 · Late-Breaking
P65-047，一种新型TEAD降解剂，通过破坏Hippo通路克服NSCLC中的KRAS抑制剂耐药
P65-047, a novel TEAD degrader, overcomes KRAS inhibitor resistance through Hippo pathway disruption in NSCLC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：等位基因特异性KRAS抑制剂（如MRTX849、MRTX1133）在KRAS突变型NSCLC中显示出临床获益，但面临由适应性YAP/TEAD轴激活介导的快速耐药发展。TEAD降解剂代表了一种合理的机制性联用伙伴，可拦截这一旁路通路并恢复KRAS抑制剂的敏感性。
方法：P65-047，一种招募cereblon的TEAD降解剂，在以下模型中进行评估：（1）使用NCI-H226（NF2−/− 间皮瘤，Hippo失调）和CALU-1（KRAS G12C/TP53−/− NSCLC）的体内皮下CDX模型；以及（2）体外KRAS G12D(LA1)/p53 R172HΔG/+（KP）同基因NSCLC小鼠模型，包括344SQ-G12D和344SQ-G12C（经CRISPR/Cas9修饰为KRAS G12C）。使用了亲本细胞及MRTX1133/MRTX849耐药衍生细胞。通过蛋白质印迹和qPCR评估TEAD蛋白降解和靶基因抑制。
结果：P65-047单药治疗在两个异种移植模型中均诱导剂量依赖性肿瘤消退（载体处理的肿瘤则进展）。在耐药细胞模型中，P65-047表现出极小的单药活性，但在联合治疗情境中产生了KRAS抑制剂依赖性生长抑制的显著恢复：P65-047 + MRTX1133使MRTX1133耐药的344SQ-M1133R细胞重新敏感，P65-047 + MRTX849在细胞活力检测中使MRTX849耐药的344SQ-M849R细胞重新敏感。机制研究证实了在耐药细胞中的靶向性TEAD降解和TEAD调控转录本的抑制。
结论：P65-047展现出高疗效，在体内提供强劲的肿瘤消退，在体外提供强效的重新敏感化，确立了TEAD降解作为一种经机制验证的策略，用于克服KRAS突变型NSCLC中的获得性耐药。这些数据支持TEAD降解剂在等位基因特异性KRAS抑制剂难治性疾病患者中的临床推进。
查看英文原文 English abstract
Background: Allele-specific KRAS inhibitors (e.g. MRTX849, MRTX1133) show clinical benefit in KRAS-mutant NSCLC but face rapid development of resistance mediated by adaptive YAP/TEAD axis activation. TEAD degraders represent a rational mechanistic partner to intercept this bypass pathway and restore KRAS inhibitor sensitivity.
Methods: P65-047, a cereblon-recruiting TEAD degrader, was evaluated in: (1) in vivo subcutaneous CDX models using NCI-H226 (NF2 -/- mesothelioma, Hippo-dysregulated) and CALU-1 (KRAS G12C /TP53 -/- NSCLC); and (2) in vitro KRAS G12D(LA1) /p53 R172HΔG/+ (KP) syngeneic NSCLC mouse models including 344SQ-G12D and 344SQ-G12C (CRISPR/Cas9 modified to KRAS G12C ). Parental and MRTX1133/MRTX849-resistant derivatives were utilized. TEAD protein degradation and target gene suppression were assessed by Western blot and qPCR.
Results: P65-047 monotherapy induced dose-dependent tumour regression in both xenograft models (vehicle-treated tumours progressed). In resistant cell models, P65-047 exhibited minimal single-agent activity but produced marked restoration of KRAS inhibitor-dependent growth suppression in combination settings: P65-047 + MRTX1133 resensitized MRTX1133-resistant 344SQ-M1133R cells, and P65-047 + MRTX849 resensitized MRTX849-resistant 344SQ-M849R cells in cell viability assays. Mechanistic studies confirmed on-target TEAD degradation and suppression of TEAD-regulated transcripts in resistant cells.
Conclusions: P65-047 displays high efficacy, delivering robust in vivo tumour regression and strong resensitization in vitro , establishing TEAD degradation as a mechanistically validated strategy to overcome acquired resistance in KRAS-mutant NSCLC. These data support clinical advancement of TEAD degraders in patients with allele-specific KRAS inhibitor-refractory disease.
利益披露 Disclosure
R. Sawant,
Beactica Therapeutics Employment, Stock Option, Patent.
M. Geitmann,
Beactica Therapeutics Employment, Stock, Stock Option.
P. Källblad,
Beactica Therapeutics Employment, Stock.
S. T. Kundu,
UT MD Anderson Cancer Center Employment.
S. Garza,
UT MD Anderson Cancer Center Employment.
D. L. Gibbons,
UT MD Anderson Cancer Center Employment.
K. Koehler,
Beactica Therapeutics Employment, Stock Option.
P. Brandt,
Beactica Therapeutics Employment, Stock Option, Patent.