Cancer Research Program, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM)-CIBERONC, Barcelona, Spain.
Department of Medical Oncology, Hospital del Mar-CIBERONC, Barcelona, Spain.
Mol Cancer Ther. 2019 Nov;18(11):2135-2145. doi: 10.1158/1535-7163.MCT-19-0455. Epub 2019 Sep 4.
Despite the clinical benefit of trastuzumab, eventually all HER2-amplified gastric cancer tumors develop drug resistance. We aimed to identify molecular mechanisms of acquired resistance to trastuzumab in gastric cancer by using well-established cell line-based preclinical models, as well as samples from patients with HER2-positive gastric cancer treated with trastuzumab. We studied trastuzumab resistance in NCI-N87 and OE19, two gastric cancer cell lines that overexpress HER2 receptor and are trastuzumab sensitive. Differences at protein, DNA, and RNA levels between the parental and resistant cells were characterized and functional studies were performed. Paired pre- and post-trastuzumab blood and tissue samples from patients with gastric cancer treated with trastuzumab were analyzed. We found that resistant cells were associated with increased activation of MAPK/ERK and PI3K/mTOR pathways driven by SRC activation. Upstream, resistant cells showed increased coexpression of multiple HER-family ligands that allowed for compensatory activation of alternative HER receptors upon HER2 blockade. Simultaneous inhibition of EGFR, HER2, and HER3 by the novel antibody mixture, Pan-HER, effectively reverted trastuzumab resistance and Similarly, an increase in HER-family ligands was observed in serum and tumor from patients with gastric cancer after trastuzumab therapy. We propose that trastuzumab resistance in gastric cancer is mediated by HER-family ligand upregulation that allows a compensatory activation of HER receptors and maintains downstream signaling activation despite trastuzumab therapy. Resistance is reverted by simultaneous inhibition of EGFR, HER2, and HER3, thereby revealing a potential therapeutic strategy to overcome trastuzumab resistance in patients with gastric cancer.
尽管曲妥珠单抗具有临床获益，但最终所有 HER2 扩增的胃癌肿瘤都会产生耐药性。我们旨在通过使用成熟的基于细胞系的临床前模型以及接受曲妥珠单抗治疗的 HER2 阳性胃癌患者的样本，来确定胃癌对曲妥珠单抗获得性耐药的分子机制。我们研究了 NCI-N87 和 OE19 这两种过表达 HER2 受体且对曲妥珠单抗敏感的胃癌细胞系中曲妥珠单抗耐药的机制。对亲本细胞和耐药细胞在蛋白质、DNA 和 RNA 水平上的差异进行了表征，并进行了功能研究。分析了接受曲妥珠单抗治疗的胃癌患者治疗前后的配对血液和组织样本。我们发现耐药细胞与 SRC 激活驱动的 MAPK/ERK 和 PI3K/mTOR 通路的过度激活有关。在其上游，耐药细胞表现出多种 HER 家族配体的共表达增加，这使得在 HER2 阻断时能够代偿性地激活替代的 HER 受体。新型抗体混合物 Pan-HER 同时抑制 EGFR、HER2 和 HER3，可有效逆转曲妥珠单抗耐药性，并且在接受曲妥珠单抗治疗后，胃癌患者的血清和肿瘤中也观察到 HER 家族配体的增加。我们提出，胃癌中曲妥珠单抗耐药是由 HER 家族配体的上调介导的，这允许 HER 受体的代偿性激活，并在曲妥珠单抗治疗的情况下维持下游信号的激活。通过同时抑制 EGFR、HER2 和 HER3 可以逆转耐药性，从而揭示了一种潜在的治疗策略，以克服胃癌患者对曲妥珠单抗的耐药性。
