State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Aging (Albany NY). 2022 Apr 25;14(8):3597-3606. doi: 10.18632/aging.204031.
Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy and lacks effective therapeutic targets. Trametinib is considered to be a promising potential indirectly targeted KRAS inhibitor in PDAC. However, the clinical outcomes were poor. JQ1 displayed a significant synergistic effect when combined with chemotherapy or potential targeted therapy in pancreatic cancer. The impact of Trametinib and JQ1 combination treatment in PDAC remains to be fully elucidated.
The efficacy of trametinib and JQ1 on cell proliferation and cytotoxicity was assayed in 7 mutant pancreatic cancer cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using a luminescent cell viability assay. Immunoblot analysis was carried out to investigate changes in p62 and autophagy.
We found that either trametinib or JQ1 alone inhibited the proliferation of some pancreatic cancer cell lines with alterations, irrespective of the mutational loci of and the aberrant status of the other driver genes. The synergistic effects of combination treatment of trametinib and JQ1 were observed in both trametinib-resistant and trametinib-sensitive cells. In trametinib-sensitive PDAC cells, the combined treatment definitely inhibited p62 expression compared with trametinib alone, while LC3 expression at high levels changed little. In trametinib-resistant PDAC cells, the combination of MEK/BET inhibitor dramatically decreased p62 expression compared with single agent, while p62 expression increased after anti-autophagic therapy was added.
Blocking RAS downstream signaling and epigenetic pathway synergistically increases the antiproliferative activity in mutant PDAC cells. Combination therapeutic synergism may induce different cell death modes in different pancreatic cancer subtypes.
胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，缺乏有效的治疗靶点。曲美替尼被认为是 PDAC 中一种有前途的潜在间接靶向 KRAS 抑制剂。然而，临床结果不佳。JQ1 在胰腺癌中与化疗或潜在靶向治疗联合显示出显著的协同作用。曲美替尼和 JQ1 联合治疗在 PDAC 中的影响仍有待充分阐明。
在 7 种突变胰腺癌细胞系中测定曲美替尼和 JQ1 对细胞增殖和细胞毒性的疗效。使用发光细胞活力测定法评估单独或联合使用药物的细胞毒性作用。进行免疫印迹分析以研究 p62 和自噬的变化。
我们发现，无论是曲美替尼还是 JQ1 单独治疗，都能抑制一些改变的胰腺癌细胞系的增殖，而与 和其他驱动基因的异常状态的突变部位无关。在曲美替尼耐药和敏感的 PDAC 细胞中都观察到曲美替尼和 JQ1 联合治疗的协同作用。在曲美替尼敏感的 PDAC 细胞中，与单独使用曲美替尼相比，联合治疗肯定会抑制 p62 的表达，而高水平的 LC3 表达变化不大。在曲美替尼耐药的 PDAC 细胞中，MEK/BET 抑制剂联合治疗与单独用药相比显著降低了 p62 的表达，而加入抗自噬治疗后 p62 的表达增加。
阻断 RAS 下游信号和表观遗传途径协同增加了 突变 PDAC 细胞的增殖抑制活性。联合治疗的协同作用可能在不同的胰腺癌亚型中诱导不同的细胞死亡模式。
