在美国，三阴性乳腺癌 (TNBC) 占乳腺癌病例的 15-20%。全身新辅助化疗 (NACT)，无论是否联合免疫治疗，都是早期 TNBC 患者目前的标准治疗方法。然而，一旦 NACT 完成，高达 70% 的 TNBC 患者会出现明显的残留病灶，这与手术切除后两到三年内复发的高风险相关。为了确定耐药 TNBC 的可靶向脆弱性，我们在患者接受 NACT 之前和之后从 TNBC 肿瘤中生成了纵向患者衍生异种移植 (PDX) 模型。然后，我们编译了所有模型的转录组和药物反应概况。转录组分析发现，相对于 NACT 之前的肿瘤，NACT 后肿瘤模型中异常蛋白稳态途径的富集。这一观察结果与体外对针对蛋白酶体、热休克蛋白和neddylation途径的抑制剂的敏感性增加相关。 Pevonedistat 是一种被注释为 NEDD8 激活酶 (NAE) 抑制剂的药物，优先进行体内验证，并在 TNBC 的多个 PDX 模型中证明了作为单一药物的功效。药物转录组学分析确定了 pevonedistat 活性和翻译后修饰 (PTM) 机制之间的通路水平相关性，特别是涉及 neddylation 和 sumoylation 靶点。与体内反应较差的模型相比，在对 pevonedistat 表现出良好反应的模型中观察到 NEDD8 和 SUMO1 水平升高。此外，neddylation 调节途径的表达与肿瘤对 pevonedistat 的反应之间出现了相关性，表明针对这些 PTM 途径可能会有效对抗化疗耐药性 TNBC。© 2024。作者。

Triple negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases in the United States. Systemic neoadjuvant chemotherapy (NACT), with or without immunotherapy, is the current standard of care for patients with early-stage TNBC. However, up to 70% of TNBC patients have significant residual disease once NACT is completed, which is associated with a high risk of developing recurrence within two to three years of surgical resection. To identify targetable vulnerabilities in chemoresistant TNBC, we generated longitudinal patient-derived xenograft (PDX) models from TNBC tumors before and after patients received NACT. We then compiled transcriptomes and drug response profiles for all models. Transcriptomic analysis identified the enrichment of aberrant protein homeostasis pathways in models from post-NACT tumors relative to pre-NACT tumors. This observation correlated with increased sensitivity in vitro to inhibitors targeting the proteasome, heat shock proteins, and neddylation pathways. Pevonedistat, a drug annotated as a NEDD8-activating enzyme (NAE) inhibitor, was prioritized for validation in vivo and demonstrated efficacy as a single agent in multiple PDX models of TNBC. Pharmacotranscriptomic analysis identified a pathway-level correlation between pevonedistat activity and post-translational modification (PTM) machinery, particularly involving neddylation and sumoylation targets. Elevated levels of both NEDD8 and SUMO1 were observed in models exhibiting a favorable response to pevonedistat compared to those with a less favorable response in vivo. Moreover, a correlation emerged between the expression of neddylation-regulated pathways and tumor response to pevonedistat, indicating that targeting these PTM pathways may prove effective in combating chemoresistant TNBC.© 2024. The Author(s).