Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
Mol Cancer Ther. 2021 Apr;20(4):641-654. doi: 10.1158/1535-7163.MCT-20-0531. Epub 2021 Feb 3.
gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with -mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of -mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and-equally important-to identify biomarkers for patient stratification.
基因突变是肺癌中最常见的致癌事件。它们激活了多个以 RAS 为中心的信号通路，其中包括 MAPK、PI3K 和 RB 通路。在 MAPK 通路中，ERK1/2 蛋白在传递有丝分裂信号和激活细胞质和核靶标方面发挥着瓶颈作用。鉴于 - 突变型肺癌患者持续应用 MEK 抑制剂的抗肿瘤活性和毒性令人失望，研究最近集中在 ERK1/2 蛋白作为治疗靶点，以及 ERK 抑制剂防止旁路和反馈通路激活的能力上。在这里，我们表明新型选择性 ATP 竞争性 ERK1/2 抑制剂 LY3214996 的间歇性应用在 - 突变型肺癌患者来源的异种移植（PDX）模型中发挥了单药活性。联合治疗耐受性良好，并导致 PDX 模型中协同（ERKi 加 PI3K/mTORi LY3023414）和相加（ERKi 加 CDK4/6i abemaciclib）的肿瘤生长抑制。需要进行未来的临床试验来研究基于间歇性 ERK 抑制剂的治疗方案是否可以克服连续 MEK 抑制观察到的毒性，并且同样重要的是确定患者分层的生物标志物。
