Li Dandan, Lo Winifred, Rudloff Udo
Thoracic & Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Clin Transl Med. 2018 Feb 22;7(1):7. doi: 10.1186/s40169-018-0184-7.
Hereditary diffuse gastric cancer is a cancer predisposition syndrome associated with germline mutations of the E-cadherin gene (CDH1; NM_004360). Male CDH1 germline mutation carriers have by the age of 80 years an estimated 70% cumulative incidence of gastric cancer, females of 56% for gastric and of 42% for lobular breast cancer. Metastatic HDGC has a poor prognosis which is worse than for sporadic gastric cancer. To date, there have been no treatment options described tailored to this molecular subtype of gastric cancer. Here we review recent differential drug screening and gene expression results in c.1380del CDH1-mutant HDGC cells which identified drug classes targeting PI3K (phosphoinositide 3-kinase), MEK (mitogen-activated protein kinase), FAK (focal adhesion kinase), PKC (protein kinase C), and TOPO2 (topoisomerase II) as selectively more effective in cells with defective CDH1 function. ERK1-ERK2 (extracellular signal regulated kinase) signaling measured as top enriched network in c.1380delA CDH1-mutant cells. We compared these findings to synthetic lethality and pharmacological screening results in isogenic CDH1 MCF10A mammary epithelial cells with and without CDH1 expression and current knowledge of E-cadherin/catenin-EGFR cross-talk, and suggest different rationales how loss of E-cadherin function activates PI3K, mTOR, EGFR, or FAK signaling. These leads represent molecularly selected treatment options tailored to the treatment of CDH1-deficient familial gastric cancer.
遗传性弥漫性胃癌是一种癌症易感性综合征，与E-钙黏蛋白基因（CDH1；NM_004360）的种系突变相关。男性CDH1种系突变携带者到80岁时，估计胃癌累积发病率为70%，女性患胃癌的累积发病率为56%，患小叶性乳腺癌的累积发病率为42%。转移性遗传性弥漫性胃癌预后较差，比散发性胃癌更差。迄今为止，尚未有针对这种分子亚型胃癌的治疗方案描述。在此，我们综述了最近在c.1380del CDH1突变的遗传性弥漫性胃癌细胞中的差异药物筛选和基因表达结果，这些结果确定了靶向PI3K（磷脂酰肌醇3-激酶）、MEK（丝裂原活化蛋白激酶）、FAK（粘着斑激酶）、PKC（蛋白激酶C）和TOPO2（拓扑异构酶II）的药物类别在CDH1功能缺陷的细胞中选择性地更有效。在c.1380delA CDH1突变细胞中，ERK1-ERK2（细胞外信号调节激酶）信号传导作为最富集的网络被检测到。我们将这些发现与有或无CDH1表达的同基因CDH1 MCF10A乳腺上皮细胞中的合成致死性和药理学筛选结果以及E-钙黏蛋白/连环蛋白-表皮生长因子受体相互作用的现有知识进行了比较，并提出了不同的理论依据，说明E-钙黏蛋白功能丧失如何激活PI3K、mTOR、表皮生长因子受体或FAK信号传导。这些线索代表了针对CDH1缺陷型家族性胃癌治疗的分子选择治疗方案。
