Huntsman Cancer Institute, University of Utah , Salt Lake City, UT, USA.
Department of Oncological Sciences, University of Utah , Salt Lake City, UT, USA.
J Exp Med. 2023 Mar 6;220(3). doi: 10.1084/jem.20221524. Epub 2023 Jan 31.
Pharmacological inhibition of KRAS>RAF>MEK1/2>ERK1/2 signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDAC). Interestingly, combined inhibition of MEK1/2 (with trametinib [T]) plus autophagy (with chloroquine [CQ] or hydroxychloroquine [HCQ]) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDAC cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ-resistant PDAC tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of P/HCQ.
KRAS>RAF>MEK1/2>ERK1/2 信号的药理学抑制未能给胰腺导管腺癌 (PDAC) 患者带来临床获益。有趣的是，MEK1/2 联合抑制（用曲美替尼[T]）加自噬（用氯喹 [CQ] 或羟氯喹 [HCQ]）在临床前模型和一名患者（患者 1）中显示出显著的抗肿瘤作用。然而，并非所有患者对 T/HCQ 方案都有反应，并且患者 1最终发展出耐药性疾病。在这里，我们报告原发性或获得性耐药与包含 c-MYC 的局部 DNA 拷贝数增益有关。此外，c-MYC 在 PDAC 细胞系中的异位表达使它们对 T/HCQ 耐药。有趣的是，CDK4/6 抑制剂 palbociclib (P) 也诱导自噬并克服了 c-MYC 介导的 T/HCQ 耐药性，使得 P/HCQ 促进了具有高表达 c-MYC 的 T/HCQ 耐药 PDAC 肿瘤的消退。最后，P/HCQ 治疗患者 1 导致生化疾病反应。这些数据表明，c-MYC 表达升高既是 T/HCQ 耐药性的标志物，也是其介导因素，可通过使用 P/HCQ 来克服。
