Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
Nat Med. 2019 Apr;25(4):628-640. doi: 10.1038/s41591-019-0368-8. Epub 2019 Mar 4.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.
胰腺导管腺癌 (PDAC) 的特征是 KRAS 和自噬依赖性肿瘤生长，但 KRAS 在支持自噬中的作用尚未确定。令我们惊讶的是，我们发现抑制 KRAS 会增加自噬通量，其效应因子 ERK MAPK 的药理学抑制也是如此。此外，我们证明，无论是 KRAS 抑制还是 ERK 抑制，都会降低糖酵解和线粒体功能。我们推测，ERK 抑制可能通过损害其他 KRAS 或 ERK 驱动的代谢过程，从而增强 PDAC 对自噬的依赖性。因此，我们发现自噬抑制剂氯喹和特定自噬调节剂的基因或药理学抑制与 ERK 抑制剂协同增强了 ERK 抑制剂在 KRAS 驱动的 PDAC 中介导抗肿瘤活性的能力。我们的结论是，同时阻断 ERK MAPK 和 ERK 抑制上调的自噬过程的药理学抑制剂组合可能是治疗 PDAC 的有效方法。
