Purpose: TGFβ signaling is implicated in the progression of most cancers, including esophageal adenocarcinoma (EAC). Emerging evidence indicates that TGFβ signaling is a key factor in the development of resistance toward cancer therapy. Experimental Design: In this study, we developed patient-derived organoids and patient-derived xenograft models of EAC and performed bioinformatics analysis combined with functional genetics to investigate the role of SMAD family member 3 (SMAD3) in EAC resistance to oxaliplatin. Results: Chemotherapy nonresponding patients showed enrichment of SMAD3 gene expression when compared with responders. In a randomized patient-derived xenograft experiment, SMAD3 inhibition in combination with oxaliplatin effectively diminished tumor burden by impeding DNA repair. SMAD3 interacted directly with protein phosphatase 2A (PP2A), a key regulator of the DNA damage repair protein ataxia telangiectasia mutated (ATM). SMAD3 inhibition diminished ATM phosphorylation by enhancing the binding of PP2A to ATM, causing excessive levels of DNA damage. Conclusions: Our results identify SMAD3 as a promising therapeutic target for future combination strategies for the treatment of patients with EAC.

中文翻译：

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靶向 SMAD3 通过阻碍 DNA 修复来改善食管腺癌模型对奥沙利铂的反应

目的：TGFβ 信号传导与大多数癌症的进展有关，包括食管腺癌 (EAC)。新的证据表明 TGFβ 信号传导是癌症治疗耐药性发展的关键因素。实验设计：在本研究中，我们开发了EAC的患者来源的类器官和患者来源的异种移植模型，并结合功能遗传学进行生物信息学分析，以研究SMAD家族成员3（SMAD3）在EAC对奥沙利铂耐药中的作用。结果：与应答者相比，化疗无应答患者的 SMAD3 基因表达丰富。在一项随机的源自患者的异种移植实验中，SMAD3 抑制与奥沙利铂联合使用，通过阻止 DNA 修复有效地减轻了肿瘤负荷。 SMAD3 直接与蛋白磷酸酶 2A (PP2A) 相互作用，蛋白磷酸酶 2A 是 DNA 损伤修复蛋白共济失调毛细血管扩张突变 (ATM) 的关键调节因子。 SMAD3 抑制通过增强 PP2A 与 ATM 的结合来减少 ATM 磷酸化，从而导致过度的 DNA 损伤。结论：我们的结果表明 SMAD3 是未来治疗 EAC 患者联合策略的一个有前途的治疗靶点。