Lin Jiunn-Chang, Liu Tsang-Pai, Yang Pei-Ming
Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei 10449, Taiwan.
Mackay Junior College of Medicine, Nursing and Management, New Taipei City 11260, Taiwan.
J Clin Med. 2020 Dec 12;9(12):4019. doi: 10.3390/jcm9124019.
The mutation of cyclin dependent kinase inhibitor 2A (CDKN2A) is frequently found in pancreatic ductal adenocarcinoma (PDAC). However, its prognostic and therapeutic roles in PDAC have not been extensively investigated yet. In this study, we mined and integrated the cancer genomics and chemogenomics data to investigate the roles of CDKN2A genetic alterations in PDAC patients' prognosis and treatment. We found that functional CDKN2A inactivation caused by mutations and deep deletions predicted poor prognosis in PDAC patients. CDKN2A inactivation was associated with the upregulation of genes related to estrogen response, which can be overcome by CDKN2A restoration. Chemosensitivity profiling of PDAC cell lines and patient-derived organoids found that CDKN2A inactivation was associated with the increased sensitivity to paclitaxel and SN-38 (the active metabolite of irinotecan). However, only paclitaxel can mimic the effect of CDKN2A restoration, and its drug sensitivity was correlated with genes related to estrogen response. Therefore, our study suggested that CDKN2A-inactivated PDAC patients could benefit from the precision treatment with paclitaxel, whose albumin-stabilized nanoparticle formulation (nab-paclitaxel) has been approved for treating PDAC.
细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）的突变在胰腺导管腺癌（PDAC）中经常被发现。然而，其在PDAC中的预后和治疗作用尚未得到广泛研究。在本研究中，我们挖掘并整合了癌症基因组学和化学基因组学数据，以研究CDKN2A基因改变在PDAC患者预后和治疗中的作用。我们发现，由突变和深度缺失导致的功能性CDKN2A失活预示着PDAC患者预后不良。CDKN2A失活与雌激素反应相关基因的上调有关，而CDKN2A的恢复可以克服这种上调。对PDAC细胞系和患者来源类器官的化学敏感性分析发现，CDKN2A失活与对紫杉醇和SN-38（伊立替康的活性代谢产物）的敏感性增加有关。然而，只有紫杉醇能够模拟CDKN2A恢复的效果，并且其药物敏感性与雌激素反应相关基因有关。因此，我们的研究表明，CDKN2A失活的PDAC患者可能从紫杉醇的精准治疗中获益，其白蛋白稳定纳米颗粒制剂（纳米白蛋白结合型紫杉醇）已被批准用于治疗PDAC。
