Medical Scientist Training Program, University of Michigan, Ann Arbor, USA.
Department of Surgery, University of Michigan Cancer Center, University of Michigan, 1500 East Medical Center Drive, Cancer Center Room 6306, Ann Arbor, MI, 48109-0944, USA.
Sci Rep. 2020 Jul 7;10(1):11133. doi: 10.1038/s41598-020-67814-9.
Pancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. KRAS is the most commonly mutated gene in pancreatic cancer, but clinical agents that directly target mutant KRAS are not available. Several effector pathways are activated downstream of oncogenic Kras, including MAPK signaling. MAPK signaling can be inhibited by targeting MEK1/2; unfortunately, this approach has been largely ineffective in pancreatic cancer. Here, we set out to identify mechanisms of MEK inhibitor resistance in pancreatic cancer. We optimized the culture of pancreatic tumor 3D clusters that utilized Matrigel as a basement membrane mimetic. Pancreatic tumor 3D clusters recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the clusters with trametinib, a MEK inhibitor, had only a modest effect on these cultures. We observed that cells adjacent to the basement membrane mimetic Matrigel survived MEK inhibition, while the cells in the interior layers underwent apoptosis. Our findings suggested that basement membrane attachment provided survival signals. We thus targeted integrin β1, a mediator of extracellular matrix contact, and found that combined MEK and integrin β1 inhibition bypassed trametinib resistance. Our data support exploring integrin signaling inhibition as a component of combination therapy in pancreatic cancer.
胰腺癌是人类最致命的恶性肿瘤之一，其 5 年生存率仅为 9%。KRAS 是胰腺癌中最常见的突变基因，但目前尚无直接针对突变 KRAS 的临床药物。致癌性 Kras 下游有几个效应途径被激活，包括 MAPK 信号通路。MAPK 信号通路可以通过靶向 MEK1/2 来抑制；然而，这种方法在胰腺癌中基本上没有效果。在这里，我们着手研究胰腺癌中 MEK 抑制剂耐药的机制。我们优化了使用 Matrigel 作为基底膜模拟物的胰腺肿瘤 3D 簇的培养。胰腺肿瘤 3D 簇再现了突变型 KRAS 的依赖性和对 MEK 抑制的抗性。用 MEK 抑制剂 trametinib 处理这些培养物，对其仅有适度的影响。我们观察到，靠近基底膜模拟物 Matrigel 的细胞在 MEK 抑制下存活，而内部层的细胞则发生凋亡。我们的发现表明，基底膜附着提供了存活信号。因此，我们针对整合素 β1 进行了研究，整合素 β1 是细胞外基质接触的介质，发现联合 MEK 和整合素 β1 抑制可绕过 trametinib 耐药性。我们的数据支持探索整合素信号抑制作为胰腺癌联合治疗的一个组成部分。
