Lulla Amriti R, Akli Said, Karakas Cansu, Ha Min Jin, Fowlkes Natalie W, Mitani Yoshitsugu, Bui Tuyen, Wang Jing, Rao Xiayu, Hunt Kelly K, Meijer Laurent, El-Naggar Adel K, Keyomarsi Khandan
Departments of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Departments of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Oncogenesis. 2021 May 14;10(5):40. doi: 10.1038/s41389-021-00324-z.
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.
涎腺癌（SGCs）是一种罕见但具有侵袭性的恶性肿瘤，组织学异质性显著，这使得预测预后和开发靶向治疗具有挑战性。在大多数患者中，局部复发和/或远处转移很常见，全身治疗对生存率的影响很小。因此，识别可作为多种组织学亚型SGCs复发预测指标的新型治疗靶点是一个尚未满足的需求领域。在本研究中，我们开发了一种新型的SGC转基因小鼠模型，有效地重现了人类SGC的主要组织学亚型（腮腺腺癌）。将CDK2基因敲除（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，该模型出现在涎腺的腮腺区域，类似于人类SGC常见的起源部位。为了鉴定LMW-E的CDK2非依赖性催化伙伴，我们在质谱分析中使用了表达LMW-E的细胞系，并在下拉试验中进行了后续的生化验证。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的人类SGC细胞增殖受到抑制。我们还提供了临床证据，证明LMW-E/CDK5共表达与人类SGC无复发生存率降低显著相关。对代表人类涎腺癌四种主要组织学亚型（腺泡细胞癌、腺样囊性癌、黏液表皮样癌和鳞状细胞癌）的424例患者进行LMW-E和CDK5的免疫组织化学分析，结果显示，70%的患者中LMW-E和CDK5呈一致（阳性/阳性或阴性/阴性）表达。LMW-E/CDK5（两者均为阳性）的共表达有力地预测了复发的可能性，无论这些肿瘤的组织学分类如何。总体而言，我们的结果表明，CDK5是治疗LMW-E过表达肿瘤的SGC患者的一种新型且可靶向的生物标志物。
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