PO.ET03.06 · 实验与分子治疗
HER3-DXd在结直肠癌PDX模型中疗效有限，揭示分子耐药机制并为合理联合策略提供依据
Limited efficacy of HER3-DXd in colorectal cancer PDX models reveals molecular resistance mechanisms and informs rational combinatorial strategies
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
HER3(ERBB3)是EGFR家族成员，通过与其他ERBB受体二聚化激活PI3K/AKT信号传导，并常与靶向治疗耐药相关。Patritumab deruxtecan是一种HER3导向的抗体-药物偶联物(ADC)，已在非小细胞肺癌和乳腺癌中显示出临床活性，近期在转移性结直肠癌(mCRC)中进行了评估。尽管HER3在mCRC中频繁表达，但其在化疗难治性疾病中的治疗意义尚未很好地界定。我们在一组17个分子特征明确的mCRC患者来源异种移植(PDX)模型中评估了HER3-DXd，其中大多数源自既往接受伊立替康治疗并对其耐药的患者。采用肿瘤生长抑制来评估应答。进行了分子特征分析（包括全外显子组测序、RNA测序和反相蛋白质阵列）以阐明耐药机制并指导合理的联合策略。单药HER3-DXd在各模型间显示出可变的活性，在表现出伊立替康耐药的模型中应答有限。HER3表达并不能一致地预测应答。对这一关联的解释可能受限于HER3阳性缺乏标准化临界值。相对权重分析结果表明，86%的应答归因于载荷敏感性，而仅13%与IHC测定的HER3表达相关。分子分析揭示无应答者中持续的PI3K/AKT和MAPK信号传导，以及上调的受体酪氨酸激酶(RTK)信号传导，并与药物外排转运体表达增加相关。功能研究表明，将HER3-DXd与MEK、WEE1或PLK1抑制剂联用产生协同抗肿瘤效应。磷酸化蛋白质组学数据支持HER3阻断后的适应性通路重连。这些发现凸显了化疗难治性mCRC中HER3信号传导的复杂性，并支持开发生物标志物驱动的联合策略，以增强HER3靶向ADC（可能还包括其他携带拓扑异构酶抑制剂载荷的ADC）在此情境下的治疗疗效。
查看英文原文 English abstract
HER3 (ERBB3), a member of the EGFR family, activates PI3K/AKT signaling through dimerization with other ERBB receptors and is frequently implicated in resistance to targeted therapies. Patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), has shown clinical activity in non-small cell lung and breast cancers, and has been recently evaluated in metastatic colorectal cancer (mCRC). Despite frequent HER3 expression in mCRC, its therapeutic relevance in chemotherapy-refractory disease is not well defined. We evaluated HER3-DXd in a panel of 17 molecularly characterized mCRC patient-derived xenograft (PDX) models, the majority of which were derived from patients previously treated with and resistant to irinotecan. Tumor growth inhibition was used to assess response. Molecular profiling (including whole-exome sequencing, RNA sequencing, and Reverse Phase Protein Array) was conducted to elucidate resistance mechanisms and direct rational combination strategies. Single-agent HER3-DXd showed variable activity across models, with limited responses in those exhibiting irinotecan resistance. HER3 expression did not consistently predict response. Interpretation of this association might be limited by the absence of a standardized cutoff for HER3 positivity. The results of the relative weight analysis indicated that 86% of the response was attributable to the payload sensitivity, while only 13% was associated with HER3 expression as determined by IHC. Molecular analyses revealed persistent PI3K/AKT and MAPK signaling in non-responders, along with upregulated receptor tyrosine kinase (RTK) signaling and a correlation with increased expression of drug efflux transporters. Functional studies demonstrated that combining HER3-DXd with MEK, WEE1, or PLK1 inhibitors produced synergistic antitumor effects. Phospho-proteomic data supported adaptive pathway rewiring following HER3 blockade. These findings highlight the complexity of HER3 signaling in chemotherapy-refractory mCRC and support the development of biomarker-driven combination strategies to enhance therapeutic efficacy of HER3-targeted ADCs (and conceivably other ADCs with topoisomerase inhibitor payload) in this setting.
利益披露 Disclosure
P. Kanikarla, None..
A. Bent, None..
K. Gale, None..
F. Gao, None..
Z. Liu, None.