Nakano Yuta, Isobe Kazutoshi, Yoshizawa Takahiro, Urabe Naohisa, Homma Sakae, Kishi Kazuma
Department of Respiratory Medicine, Toho University School of Medicine, Tokyo 143-8541, Japan.
Pharmaceutical & ADMET Research Development, Daiichi Sankyo RD Novare Co., Ltd, Tokyo 134-8630, Japan.
Oncol Lett. 2023 Jul 20;26(3):380. doi: 10.3892/ol.2023.13966. eCollection 2023 Sep.
The long non-coding RNA (lncRNA) LINC00460 is involved in tumor growth, metastasis and drug resistance. The present study investigated the clinical significance of LINC00460 expression in patients with epidermal growth factor receptor () mutation-positive lung cancer treated with osimertinib. Osimertinib-resistant cells we derived from -mutant non-small-cell lung cancer (NSCLC) cell lines, after which, small interfering RNA (siRNA)-mediated silencing and -transcribed (IVT), synthetic LINC00460 RNA transfection were used to investigate the effects of LINC00460 expression on acquired resistance to osimertinib. Reverse transcription-quantitative polymerase chain reaction was performed to evaluate LINC00460 expression in 54 samples (RNA extracted from the tumor tissues of 30 cases and cell-free RNA from 24 cases) obtained from patients with mutation-positive lung cancer who had received osimertinib as the initial treatment. The acquisition of osimertinib resistance increased the expression of LINC00460 in the -mutant NSCLC cell lines. By contrast, knockdown of LINC00460 in osimertinib-resistant cell lines increased their sensitivity to osimertinib, whereas treatment of NSCLC cells with IVT LINC00460 RNA decreased their sensitivity to osimertinib. The present study examined LINC00460 expression at the primary tumor site and demonstrated that compared with in the low-expression group (n=24), the high-expression group (n=6) had a significantly lower best overall response rate to osimertinib (16.6% vs. 60.0%; P=0.044), significantly shorter median progression-free survival (PFS; 224 days vs. 669 days; P=0.001) and significantly shorter median overall survival (724 days vs. not reached; P=0.011). Moreover, following osimertinib therapy, PFS was significantly shorter for patients with high LINC00460 expression in plasma cell-free RNA (n=12) than for those with low LINC00460 expression (n=12) (median PFS: 655 days vs. 210 days; P=0.020). In conclusion, the upregulation of LINC00460, the expression of which is implicated in osimertinib resistance, in the primary site and plasma of patients with mutation-positive lung cancer may be associated with a poor prognosis in those treated with osimertinib.
长链非编码RNA（lncRNA）LINC00460参与肿瘤生长、转移和耐药。本研究调查了LINC00460表达在接受奥希替尼治疗的表皮生长因子受体（EGFR）突变阳性肺癌患者中的临床意义。我们从EGFR突变的非小细胞肺癌（NSCLC）细胞系中获得奥希替尼耐药细胞，然后使用小干扰RNA（siRNA）介导的沉默和体外转录（IVT）合成LINC00460 RNA转染，来研究LINC00460表达对奥希替尼获得性耐药的影响。进行逆转录定量聚合酶链反应，以评估从接受奥希替尼作为初始治疗的EGFR突变阳性肺癌患者获得的54个样本（30例患者肿瘤组织中提取的RNA和24例患者的游离RNA）中LINC00460的表达。奥希替尼耐药的获得增加了EGFR突变NSCLC细胞系中LINC00460的表达。相比之下，在奥希替尼耐药细胞系中敲低LINC00460增加了它们对奥希替尼的敏感性，而用IVT LINC00460 RNA处理NSCLC细胞则降低了它们对奥希替尼的敏感性。本研究检测了原发肿瘤部位的LINC00460表达，并证明与低表达组（n = 24）相比，高表达组（n = 6）对奥希替尼的最佳总体缓解率显著更低（16.6%对60.0%；P = 0.044），中位无进展生存期（PFS）显著更短（224天对669天；P = 0.001），中位总生存期显著更短（724天对未达到；P = 0.011）。此外，奥希替尼治疗后，血浆游离RNA中LINC00460高表达患者（n = 12）的PFS显著短于LINC00460低表达患者（n = 12）（中位PFS：655天对210天；P = 0.020）。总之，LINC00460的上调（其表达与奥希替尼耐药有关）在EGFR突变阳性肺癌患者的原发部位和血浆中，可能与接受奥希替尼治疗患者的不良预后相关。
