ERK Inhibitor LY3214996-Based Treatment Strategies for RAS-Driven Lung Cancer.
ERK Inhibitor LY3214996-Based Treatment Strategies for RAS-Driven Lung Cancer.
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DOI：
10.1158/1535-7163.mct-20-0531
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发表时间：
2021-04
影响因子：
5.7
通讯作者：
Jänne PA
中科院分区：
文献类型：
--
作者：
Köhler J;Zhao Y;Li J;Gokhale PC;Tiv HL;Knott AR;Wilkens MK;Soroko KM;Lin M;Ambrogio C;Musteanu M;Ogino A;Choi J;Bahcall M;Bertram AA;Chambers ES;Paweletz CP;Bhagwat SV;Manro JR;Tiu RV;Jänne PA
RAS基因突变是肺癌中最常见的致癌事件。它们激活多个以RAS为中心的信号网络，其中包括MAPK、PI 3 K和RB通路。在MAPK通路中，ERK 1/2蛋白发挥传递促有丝分裂信号和激活胞质和核靶点的瓶颈功能。鉴于在患有KRAS突变型肺癌的患者中连续应用MEK抑制剂的令人失望的抗肿瘤活性和毒性，最近研究集中于ERK 1/2蛋白作为治疗靶点和ERK抑制剂防止旁路和反馈途径活化的能力。在这里，我们表明，间歇性应用新型和选择性ATP竞争性ERK 1/2抑制剂LY 3214996在RAS突变型肺癌的患者来源的异种移植（PDX）模型中发挥单药活性。联合治疗耐受性良好，并在PDX模型中产生协同（ERKi + PI 3 K/mTORi LY 3023414）和累加（ERKi + CDK 4/6 i abemaciclib）肿瘤生长抑制。未来的临床试验需要研究间歇性ERK通道为基础的治疗方案是否可以克服与连续MEK抑制观察到的毒性和-同样重要的-以确定生物标志物的患者分层。
RAS 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 anti-tumor activity and toxicity of continuously applied MEK inhibitors in patients with KRAS 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 RAS 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.