SHOC2 Is a Critical Modulator of Sensitivity to EGFR-TKIs in Non-Small Cell Lung Cancer Cells
SHOC2 Is a Critical Modulator of Sensitivity to EGFR-TKIs in Non-Small Cell Lung Cancer Cells
复制标题
DOI：
10.1158/1541-7786.mcr-20-0664
复制
发表时间：
2021-02-01
影响因子：
5.2
通讯作者：
Fukunaga, Koichi
中科院分区：
文献类型：
--
作者：
Terai, Hideki;Hamamoto, Junko;Fukunaga, Koichi
EGFR突变阳性的非小细胞肺癌（NSCLC）患者对EGFR-酪氨酸激酶抑制剂（EGFR-TKI）治疗反应良好;然而，由于存在对此类药物具有内在或获得性耐药的残留癌细胞，EGFR-TKI治疗无法治愈。可能增强EGFR-TKI疗效的其他治疗靶点仍然难以捉摸。使用基于CRISPR/Cas9的筛选，我们将富含亮氨酸的重复支架蛋白SHOC 2鉴定为对EGFR-TKI治疗敏感性的关键调节剂。在体外试验的基础上，我们证明了SHOC 2表达水平与EGFR-TKI的敏感性密切相关，并且SHOC 2通过SHOC 2/MRAS/PP 1c和SHOC 2/SCRIB信号传导影响NSCLC细胞对EGFR-TKI的敏感性。潜在的SHOC 2抑制剂雷公藤红素表型模拟SHOC 2耗竭。此外，我们证实SHOC 2表达水平对于体内对EGFR-TKI的敏感性是重要的。此外，IHC显示在从经历对EGFR-TKI的获得性耐药的NSCLC患者获得的肺癌组织中表达高水平SHOC 2的癌细胞的积累。这些数据表明，SHOC 2可能是NSCLC患者的治疗靶点或预测EGFR突变阳性NSCLC患者对EGFR-TKI治疗敏感性的生物标志物。我们的研究结果可能有助于改善携带EGFR突变的NSCLC患者的治疗策略。
EGFR mutation-positive patients with non-small cell lung cancer (NSCLC) respond well to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI); however, treatment with EGFR-TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this dass of drugs. Additional treatment targets that may enhance the efficacy of EGFR-TKIs remain elusive. Using a CRISPR/Cas9-based screen, we identified the leucine-rich repeat scaffold protein SHOC2 as a key modulator of sensitivity to EGFR-TKI treatment. On the basis of in vitro assays, we demonstrated that SHOC2 expression levels strongly correlate with the sensitivity to EGFR-TKIs and that SHOC2 affects the sensitivity to EGFR-TKIs in NSCLC cells via SHOC2/MRAS/PP1c and SHOC2/SCRIB signaling. The potential SHOC2 inhibitor celastrol phenocopied SHOC2 depletion. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR-TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR-TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR-TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC harboring EGFR mutations.