Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
Universidad de Buenos Aires, Consejo Nacional de investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos (CEFYBO). Facultad de Medicina. Buenos Aires, Argentina.
Clin Cancer Res. 2020 Oct 15;26(20):5506-5519. doi: 10.1158/1078-0432.CCR-20-1232. Epub 2020 Jul 15.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib.
First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids.
Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial-mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the translational activity.
We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness.
胰腺导管腺癌（PDAC）是一种致命的癌症，其存活率低于 5%。已经测试了多种化疗药物来改善患者的预后；然而，这些治疗方法的临床疗效很低。蛋白酶体抑制剂是最具争议的药物家族之一，在临床前研究中显示出了有希望的效果，但临床效果却很低。在这里，我们揭示了一个特定的转录组特征，可以区分对蛋白酶体抑制剂卡非佐米敏感的患者亚群。
首先，我们鉴定了对蛋白酶体抑制剂卡非佐米敏感的 PDAC 来源的原代细胞培养物（PDPCC）的亚群。然后，我们使用独立成分分析（ICA）在 PDPCC 的转录组上选择预测卡非佐米化学敏感性的转录组特征。最后，我们在 PDAC 活检衍生的胰腺类器官的独立队列中验证了该特征。
敏感表型的特征是与角蛋白/鳞状途径相关的基因表达水平高，上皮-间充质转化基因表达水平下调。有趣的是，卡非佐米敏感的转录组特征与蛋白酶体活性没有任何关联，但与 ATF4 和 CHOP 的表达强烈相关，ATF4 和 CHOP 是未折叠蛋白反应的关键标志物，对于触发细胞死亡程序至关重要。一致地，与耐药表型相比，敏感表型的 RNA 和蛋白质合成水平较高，最重要的是，卡非佐米诱导的细胞死亡依赖于翻译活性。
我们证明了存在一种具有特定转录组表型的卡非佐米敏感 PDAC 亚群，这可以解释这种反应性的生物学原因。
