XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from in vivo mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation of the NRG1/ERBB3 pathway in SINE-resistant cells. Depletion of ERBB3 using siRNAs restored the antitumor effect of SINE in vitro and in vivo. Furthermore, exogenous NRG1 decreased the antitumor effect of SINE in ovarian cancer cell lines with high ERBB3 expression, but not in those with low expression. These results suggest that NRG1 and ERBB3 expression is a potential biomarker of response to SINE treatment. The antitumor effect of SINE was reduced by exogenous NRG1 in an ERBB3-dependent manner. These findings suggest that NRG1 and ERBB3 are effective biomarkers that should be evaluated in future clinical trials and are relevant therapeutic targets for the treatment of SINE-resistant cancers.

中文翻译：

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NRG1/ERBB3 通路激活诱导对 XPO1 抑制剂的获得性耐药

XPO1 抑制剂已在癌症治疗中显示出前景，但对这些药物的耐药机制尚不清楚。在这项研究中，我们从体内小鼠肿瘤中建立了抗核输出 (SINE) 卵巢癌细胞系的选择性抑制剂，并使用蛋白质和基因组阵列确定了适应性 XPO1 抑制剂抗性的机制。通路分析揭示了 SINE 抗性细胞中 NRG1/ERBB3 通路的上调。使用 siRNA 去除 ERBB3 恢复了 SINE 在体外和体内的抗肿瘤作用。此外，外源性NRG1降低了SINE在ERBB3高表达的卵巢癌细胞系中的抗肿瘤作用，但在低表达的卵巢癌细胞系中没有。这些结果表明 NRG1 和 ERBB3 表达是对 SINE 治疗反应的潜在生物标志物。外源性 NRG1 以 ERBB3 依赖性方式降低了 SINE 的抗肿瘤作用。这些发现表明 NRG1 和 ERBB3 是有效的生物标志物，应在未来的临床试验中进行评估，并且是治疗 SINE 耐药癌症的相关治疗靶点。