PO.ET05.01 · 实验与分子治疗
CDK4/6抑制剂与HDAC抑制剂在胰腺癌中的协同作用可克服自噬
Synergy of a CDK4/6 inhibitor and an HDAC inhibitor in pancreatic cancer overcomes autophagy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胰腺导管腺癌（PDAC）是一种恶性侵袭性肿瘤，预后和生存率较差。PDAC的治疗耐药很常见，归因于代谢可塑性、致密的促结缔组织增生性基质、肿瘤异质性和免疫逃逸。我们之前的研究证明了泛HDAC抑制剂Panobinostat（Pan）与CDK4/6抑制剂Abemaciclib（Abe）在PDAC细胞中的协同作用和疗效。我们旨在阐明这些协同效应的机制，因为它们有助于提高治疗疗效和克服耐药。我们为理解Pan-Abe联合效应而进行的机制研究采用了转录组学和代谢组学实验，随后进行Seahorse分析。Abe处理导致线粒体功能障碍，而Pan处理诱导了自噬和溶酶体过程。我们随后进行了细胞生物学实验，通过荧光显微镜和Western blot评估自噬谱。Pan-Abe联合展现出代谢功能障碍，但未诱导强烈的自噬应答。有趣的是，PDAC细胞中Pan-Abe的协同作用在MIA PaCa-2肿瘤异种移植模型中得到证实。要理解自噬过程在Pan-Abe对PDAC疗效中的作用还需进一步研究。
查看英文原文 English abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a malignant aggressive tumor with a poor prognosis and survival rate. Therapy resistance in PDAC is common and is attributed to metabolic plasticity, dense desmoplastic stroma, tumor heterogeneity, and immune evasion. Our previous study demonstrated synergy and efficacy of Panobinostat (Pan), a pan-HDAC inhibitor, and Abemaciclib (Abe), a CDK4/6 inhibitor, in PDAC cells. We aimed to identify the mechanism of these synergy effects as they can help in therapy efficacy and in overcoming resistance. Our mechanistic studies to understand the combination effects of Pan-Abe utilized transcriptomics and metabolomics experiments followed by Seahorse analysis. Abe treatment resulted in mitochondrial dysfunction whereas Pan treatment induced autophagy and lysosomal processes. We followed these studies using cell biological experiments assessing autophagy profile using fluorescence microscopy and western blotting. The Pan-Abe combination demonstrated metabolic dysfunction but did not induce robust autophagy response. Interestingly, the synergy of Pan-Abe from PDAC cells was confirmed in MIA PaCa-2 tumor xenograft model. Further studies are needed to understand the role of autophagic processes in the efficacy of Pan-Abe in PDAC.
利益披露 Disclosure
V. Dukhande, None.