Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.
Clin Cancer Res. 2019 Nov 15;25(22):6742-6755. doi: 10.1158/1078-0432.CCR-19-1398. Epub 2019 Sep 6.
is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells.
We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. In addition, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignant-specific vulnerabilities.
Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies.
Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models, pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT, and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both and .
在大多数胰腺导管腺癌中发生突变。MAPK 和 PI3K-AKT 是 KRAS 的主要效应途径，但迄今为止，联合 MAPK 和 PI3K 抑制尚未显示出临床疗效。我们探索恶性细胞特有的耐药机制。
我们评估了受体酪氨酸激酶在 KPC 小鼠和胰腺导管类器官中对联合 MEK 和 AKT 抑制的反应中的表达和激活。此外，我们试图确定靶向 MEK 和 AKT 抑制诱导的耐药途径的治疗效果，以确定恶性特异性脆弱性。
联合 MEK 和 AKT 抑制适度延长了 KPC 小鼠的生存期，并增加了 Egfr 和 ErbB2 磷酸化水平。肿瘤类器官，但不是其正常对应物，在 MEK 和 AKT 阻断后表现出 ERBB2 和 ERBB3 的磷酸化水平升高。泛 ERBB 抑制剂与 MEK 和 AKT 抑制剂在人 PDA 类器官中协同作用，而 EGFR 抑制剂厄洛替尼则没有观察到这种作用。在短期干预研究中，联合 MEK 和 ERBB 抑制剂治疗人类类器官原位异种移植足以引起肿瘤消退。
对正常和肿瘤胰腺类器官的分析表明，在 MEK 和 AKT 阻断期间 ERBB 激活的重要性主要在恶性培养物中。正常类器官中没有 ERBB 过度激活表明治疗指数更大。在我们的模型中，泛 ERBB 抑制剂与 MEK 和 AKT 双重抑制具有协同作用，泛 ERBB 抑制剂与 MEK 拮抗剂的组合在和均显示出最高的活性。
