Benti Senyi, Tiwari Purushottam B, Goodlett Dustin W, Daneshian Leily, Kern Grant B, Smith Mark D, Uren Aykut, Chruszcz Maksymilian, Shimizu Linda S, Upadhyay Geeta
Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA.
Cancers (Basel). 2020 Feb 22;12(2):509. doi: 10.3390/cancers12020509.
Elevated gene expression of Lymphocyte antigen 6K (LY6K) in cancer cells is associated with poor survival outcomes in multiple different cancer types including cervical, breast, ovarian, lung, and head and neck cancer. Since inhibition of LY6K expression inhibits cancer cell growth, we set out to explore whether pharmacological inhibition of LY6K could produce the same effect. We screened small molecule libraries for direct binding to recombinant LY6K protein in a surface plasmon resonance assay. We found that NSC243928 directly binds to the full-length and mature forms of LY6K and inhibits growth of HeLa cells that express LY6K. NSC243928 did not display binding with LY6D or LY6E. Our data demonstrate a first-time proof of principle study that pharmacological inhibition of LY6K using small molecules in cancer cells is a valid approach to developing targeted therapies against LY6K. This approach will be specifically relevant in hard-to-treat cancers where LY6K is highly expressed, such as cervical, pancreatic, ovarian, head and neck, lung, gastric, and triple-negative breast cancers.
癌细胞中淋巴细胞抗原6K（LY6K）的基因表达升高与多种不同癌症类型（包括宫颈癌、乳腺癌、卵巢癌、肺癌和头颈癌）的不良生存结果相关。由于抑制LY6K表达可抑制癌细胞生长，我们着手探究对LY6K进行药理学抑制是否能产生相同效果。我们在表面等离子体共振分析中筛选了小分子文库，以寻找能直接与重组LY6K蛋白结合的物质。我们发现NSC243928能直接结合LY6K的全长和成熟形式，并抑制表达LY6K的HeLa细胞的生长。NSC243928与LY6D或LY6E无结合。我们的数据首次证明了一项原理性研究，即在癌细胞中使用小分子对LY6K进行药理学抑制是开发针对LY6K的靶向疗法的有效方法。这种方法在LY6K高表达的难治性癌症（如宫颈癌、胰腺癌、卵巢癌、头颈癌、肺癌、胃癌和三阴性乳腺癌）中尤其适用。
