Salivary gland cancers (SGCs) are rare yet aggressive malignancies with significant histological heterogeneity, which has made prediction of prognosis and development of targeted therapies challenging. In majority of patients, local recurrence and/or distant metastasis are common and systemic treatments have minimal impact on survival. Therefore, identification of novel targets for treatment that can also be used as predictors of recurrence for multiple histological subtypes of SGCs is an area of unmet need. In this study, we developed a novel transgenic mouse model of SGC, efficiently recapitulating the major histological subtype (adenocarcinomas of the parotid gland) of human SGC. CDK2 knock out (KO) mice crossed with MMTV-low molecular weight forms of cyclin E (LMW-E) mice generated the transgenic mouse models of SGC, which arise in the parotid region of the salivary gland, similar to the common site of origin seen in human SGCs. To identify the CDK2 independent catalytic partner(s) of LMW-E, we used LMW-E expressing cell lines in mass spectrometric analysis and subsequent biochemical validation in pull down assays. These studies revealed that in the absence of CDK2, LMW-E preferentially binds to CDK5. Molecular targeting of CDK5, using siRNA, resulted in inhibition of cell proliferation of human SGCs overexpressing LMW-E. We also provide clinical evidence of significant association of LMW-E/CDK5 co-expression and decreased recurrence free survival in human SGC. Immunohistochemical analysis of LMW-E and CDK5 in 424 patients representing each of the four major histological subtypes of human salivary cancers (Aci, AdCC, MEC, and SDC) revealed that LMW-E and CDK5 are concordantly (positive/positive or negative/negative) expressed in 70% of these patients. The co-expression of LMW-E/CDK5 (both positive) robustly predicts the likelihood of recurrence, regardless of the histological classification of these tumors. Collectively, our results suggest that CDK5 is a novel and targetable biomarker for the treatment of patients with SGC presenting with LMW-E overexpressing tumors.

唾液腺癌 (SGC) 是一种罕见但具有显着组织学异质性的侵袭性恶性肿瘤，这使得预测预后和靶向治疗的发展具有挑战性。在大多数患者中，局部复发和/或远处转移很常见，全身治疗对生存的影响很小。因此，确定新的治疗靶点也可用作 SGC 多种组织学亚型复发的预测指标是一个未满足的需求领域。在这项研究中，我们开发了一种新型的 SGC 转基因小鼠模型，有效地概括了人类 SGC 的主要组织学亚型（腮腺腺癌）。CDK2 敲除 (KO) 小鼠与 MMTV 低分子量形式的细胞周期蛋白 E (LMW-E) 小鼠杂交产生了 SGC 转基因小鼠模型，它们出现在唾液腺的腮腺区域，类似于人类 SGC 中常见的起源部位。为了确定 LMW-E 的 CDK2 独立催化伙伴，我们在质谱分析中使用了 LMW-E 表达细胞系，并在下拉分析中使用了随后的生化验证。这些研究表明，在没有 CDK2 的情况下，LMW-E 优先与 CDK5 结合。使用 siRNA 对 CDK5 进行分子靶向，导致过表达 LMW-E 的人 SGC 的细胞增殖受到抑制。我们还提供了 LMW-E/CDK5 共表达与人类 SGC 中无复发生存率降低之间显着关联的临床证据。代表人类唾液癌四种主要组织学亚型（Aci、AdCC、MEC、和 SDC) 揭示 LMW-E 和 CDK5 在 70% 的这些患者中一致表达（阳性/阳性或阴性/阴性）。无论这些肿瘤的组织学分类如何，LMW-E/CDK5（均为阳性）的共表达有力地预测了复发的可能性。总的来说，我们的结果表明 CDK5 是一种新型的可靶向生物标志物，用于治疗呈现 LMW-E 过表达肿瘤的 SGC 患者。