Epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients respond well to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs); however, treatment with EGFR-TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class 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. Based on 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. Additionally, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR-TKIs in vivo. Furthermore, immunohistochemistry showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from NSCLC patients who experienced acquired resistance to EGFR-TKIs. These data indicate that SHOC2 may be a therapeutic target for NSCLC patients or a biomarker to predict sensitivity to EGFR-TKI therapy in EGFR mutation-positive NSCLC patients. Our findings may help improve treatment strategies for NSCLC patients harboring EGFR mutations. Implications: This study showed that SHOC2 works as a modulator of sensitivity to EGFR-TKIs and the expression levels of SHOC2 can be used as a biomarker for sensitivity to EGFR-TKIs.

中文翻译：

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SHOC2 是非小细胞肺癌细胞中 EGFR-TKI 敏感性的关键调节剂

表皮生长因子受体（EGFR）突变阳性非小细胞肺癌（NSCLC）患者对EGFR-酪氨酸激酶抑制剂（EGFR-TKIs）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性的残留癌细胞，因此用 EGFR-TKI 治疗并不能治愈。可能提高 EGFR-TKIs 疗效的其他治疗目标仍然​​难以捉摸。使用基于 CRISPR/Cas9 的筛选，我们确定富含亮氨酸的重复支架蛋白 SHOC2 作为对 EGFR-TKI 治疗敏感性的关键调节剂。基于体外测定，我们证明 SHOC2 表达水平与对 EGFR-TKI 的敏感性密切相关，并且 SHOC2 通过 SHOC2/MRAS/PP1c 和 SHOC2/SCRIB 信号传导影响 NSCLC 细胞对 EGFR-TKI 的敏感性。潜在的 SHOC2 抑制剂 celastrol 表型复制 SHOC2 耗竭。此外，我们证实 SHOC2 表达水平对于体内 EGFR-TKI 的敏感性很重要。此外，免疫组织化学显示，在对 EGFR-TKI 获得性耐药的 NSCLC 患者获得的肺癌组织中，表达高水平 SHOC2 的癌细胞积聚。这些数据表明，SHOC2 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。我们的发现可能有助于改善携带 EGFR 突变的 NSCLC 患者的治疗策略。意义：本研究表明，SHOC2 可作为对 EGFR-TKI 敏感性的调节剂，并且 SHOC2 的表达水平可用作对 EGFR-TKI 敏感性的生物标志物。