Laboratory for Developmental Genetics, USC, Los Angeles, CA 90089-0641, USA.
Exp Mol Pathol. 2013 Apr;94(2):386-97. doi: 10.1016/j.yexmp.2013.01.005. Epub 2013 Feb 8.
Mucoepidermoid carcinoma (MEC) is the most common malignant tumor originating in major and minor salivary glands (SGs). Although the precise multifactorial etiology of human SG-MEC is largely unknown, we have recently shown that cytomegalovirus (CMV) is an important component of MEC tumorigenesis. Despite the well-documented overexpression of the EGFR → ERK signaling pathway in SG-MEC, there has been limited to no clinical success with inhibition of this pathway. Using our previously characterized mouse model of CMV-induced SG dysplasia/neoplasia, we report that inhibitors of the EGFR → ERK pathway do not ameliorate or rescue well-established pathology, either singly or in combination, but they do inhibit the evolution of progressive pathogenesis ("disease tolerance") in the face of mounting CMV burden. Failure to rescue SG pathology, suggested a possible increase in the ligand levels of alternative pathways that share cell proliferation and survival effectors (e.g. ERK and PI3K). Here we present evidence of a highly significant upregulation of ligands for the EGFR, FGFR, IL-6R, and TNFR signaling pathways, all of which converge upon the Raf/MEK/ERK amplifier module. This explains our finding that even in the presence of the highest nontoxic dose of an ERK phosphorylation inhibitor, pERK is undiminished. Given the considerable pathway crosstalk, a deep understanding of subversion and dysregulation of the SG interactome by CMV is a priori quite daunting. Circumventing this dilemma, we present evidence that concurrent inhibition of ERK phosphorylation (U0126) and CMV replication (acyclovir) obviates progressive pathogenesis and results in complete SG rescue (tumor regression). These findings provide a mechanistic foundation for potential clinical trials that utilize similar concurrent treatment with extant FDA-approved drugs.
黏液表皮样癌（MEC）是最常见的来源于大、小唾液腺（SGs）的恶性肿瘤。虽然人类 SG-MEC 的多因素病因在很大程度上尚不清楚，但我们最近表明巨细胞病毒（CMV）是 MEC 肿瘤发生的重要组成部分。尽管 EGFR→ERK 信号通路在 SG-MEC 中的过度表达已有充分记录，但抑制该通路的临床效果有限或没有。利用我们之前表征的 CMV 诱导的 SG 发育不良/肿瘤发生的小鼠模型，我们报告称，EGFR→ERK 通路的抑制剂无论单独使用还是联合使用，都不能改善或挽救已建立的病理学，但它们确实抑制了在 CMV 负担不断增加的情况下进行的进行性发病机制的演变（“疾病耐受”）。未能挽救 SG 病理学表明，替代途径的配体水平可能会增加，这些途径具有细胞增殖和存活效应物（例如 ERK 和 PI3K）。在这里，我们提供了证据表明，EGFR、FGFR、IL-6R 和 TNFR 信号通路的配体高度上调，所有这些通路都集中在 Raf/MEK/ERK 放大器模块上。这解释了我们的发现，即使在存在最高非毒性剂量的 ERK 磷酸化抑制剂的情况下，pERK 也没有减少。鉴于相当大的途径串扰，CMV 对 SG 相互作用组的颠覆和失调的深入了解是相当艰巨的。为了规避这一困境，我们提供的证据表明，同时抑制 ERK 磷酸化（U0126）和 CMV 复制（阿昔洛韦）可以避免进行性发病机制并导致完全的 SG 挽救（肿瘤消退）。这些发现为利用现有 FDA 批准药物进行类似的同时治疗的潜在临床试验提供了机制基础。
