Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia.
School of Medicine, International Medical University, Kuala Lumpur, Malaysia.
Cancer Lett. 2021 Apr 28;504:81-90. doi: 10.1016/j.canlet.2021.02.006. Epub 2021 Feb 13.
Despite recent in advances in the management of nasopharyngeal carcinoma (NPC), development of targeted therapy remains challenging particularly in patients with recurrent or metastatic disease. To search for clinically relevant targets for the treatment of NPC, we carried out parallel genome-wide functional screens to identified essential genes that are required for NPC cells proliferation and cisplatin resistance. We identified lymphocyte-specific protein tyrosine kinase (LCK) as a key vulnerability of both proliferation and cisplatin resistance. Depletion of endogenous LCK or treatment of cells with LCK inhibitor induced tumor-specific cell death and synergized cisplatin sensitivity in EBV-positive C666-1 and EBV-negative SUNE1 cells. Further analyses demonstrated that LCK is regulating the proliferation and cisplatin resistance through activation of signal transducer and activator of transcription 5 (STAT5). Taken together, our study provides a molecular basis for targeting LCK and STAT5 signaling as potential druggable targets for the management of NPC.
尽管鼻咽癌（NPC）的治疗在最近取得了进展，但靶向治疗的发展仍然具有挑战性，尤其是在复发性或转移性疾病患者中。为了寻找治疗 NPC 的临床相关靶点，我们进行了平行的全基因组功能筛选，以鉴定 NPC 细胞增殖和顺铂耐药所必需的关键基因。我们发现淋巴细胞特异性蛋白酪氨酸激酶（LCK）是增殖和顺铂耐药的关键弱点。内源性 LCK 的耗竭或 LCK 抑制剂处理诱导肿瘤特异性细胞死亡，并在 EBV 阳性 C666-1 和 EBV 阴性 SUNE1 细胞中协同增强顺铂敏感性。进一步的分析表明，LCK 通过激活信号转导和转录激活因子 5（STAT5）来调节增殖和顺铂耐药性。总之，我们的研究为靶向 LCK 和 STAT5 信号提供了分子基础，可作为 NPC 管理的潜在可用药靶点。
