Department of Thorax Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
J Transl Med. 2012 Aug 30;10:180. doi: 10.1186/1479-5876-10-180.
Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models.
PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC) tissues into immunodeficient (SCID/nude) mice. HER-2 gene copy number (GCN) and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group). Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient's ESCC tissues. Similarity between the PDECX models and their corresponding patient's ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation.
None of the PDECX models (or their corresponding patient's ESCC tissues) harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+) in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+). A second HER-2 positive (IHC 2+) model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model.
This study demonstrates Trastuzumab-induced tumor regressions in HER-2 positive tumors, and highlights PIK3CA mutation as a potential resistance mechanism to Trastuzumab treatment in pre-clinical patient-derived EC xenograft models.
曲妥珠单抗目前已被批准用于治疗 HER-2 阳性肿瘤的乳腺癌和胃癌患者，但尚未用于治疗食管癌患者，这些患者的肿瘤通常显示 5%35%的 HER-2 基因扩增和 0%56%的 HER-2 蛋白表达。本研究旨在探讨曲妥珠单抗在患者来源的食管鳞状细胞癌异种移植（PDECX）小鼠模型中的治疗效果。
通过将患者食管鳞状细胞癌（ESCC）组织植入免疫缺陷（SCID/nude）小鼠中，建立 PDECX 模型。通过 FISH 和 IHC 分析，在异种移植组织和相应的患者 EC 样本中确定 HER-2 基因拷贝数（GCN）和蛋白表达。在这些 PDECX 模型中评估曲妥珠单抗的抗肿瘤疗效（n=8 只动物/组）。此外，还筛选了 PDECX 模型及其相应患者 ESCC 组织中 EGFR、K-ras、B-raf 和 PIK3CA 基因的热点突变。通过组织学、形态学、HER-2 GCN 和突变，确认 PDECX 模型与其相应患者 ESCC 组织之间的相似性。
没有一个 PDECX 模型（或其相应的患者 ESCC 组织）存在 HER-2 基因扩增。IHC 染色显示 2 个 PDECX 模型中存在 HER-2 阳性（IHC 2+），3 个 PDECX 模型中存在 HER-2 阴性。在曲妥珠单抗治疗的 EC044 HER-2 阳性模型（IHC 2+）中观察到显著的肿瘤消退。第二个 HER-2 阳性（IHC 2+）模型 EC039 携带已知的 PIK3CA 突变，并表现出 AKT 信号通路的强烈激活，对曲妥珠单抗治疗不敏感，但可以通过曲妥珠单抗和 AKT 抑制剂 AZD5363 的联合使用重新敏感。总之，我们建立了 5 个 PDECX 小鼠模型，并在 HER-2 IHC 2+模型中证明了曲妥珠单抗治疗的肿瘤消退，但在 HER-2 IHC 2+/PIK3CA 突变模型中存在耐药性。
本研究证明了曲妥珠单抗诱导的 HER-2 阳性肿瘤的肿瘤消退，并强调了 PIK3CA 突变作为曲妥珠单抗治疗临床前患者来源的 EC 异种移植模型中潜在的耐药机制。
