MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions.
MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions.
复制标题
DOI：
10.1158/1078-0432.ccr-19-3321
复制
发表时间：
2020-06-15
期刊：
影响因子：
--
通讯作者：
Somwar R
中科院分区：
文献类型：
--
作者：
Sato H;Schoenfeld AJ;Siau E;Lu YC;Tai H;Suzawa K;Kubota D;Lui AJW;Qeriqi B;Mattar M;Offin M;Sakaguchi M;Toyooka S;Drilon A;Rosen NX;Kris MG;Solit D;De Stanchina E;Davare MA;Riely GJ;Ladanyi M;Somwar R
ROS1 酪氨酸激酶抑制剂 (TKI) 对 ROS1 融合的肺腺癌患者具有显着的疗效。然而，正如所有靶向治疗所观察到的那样，会出现耐药性。检测获得性耐药 (AR) 机制对于寻找新疗法和改善患者治疗效果至关重要。 ROS1 融合体通过 cDNA 过表达（CD74/ROS1、SLC34A2/ROS1）或 CRISPR-Cas9 介导的基因组工程（EZR/ROS1）在 HBEC 和 NIH-3T3 细胞中表达。我们回顾了接受 ROS1 TKI 治疗的患者的靶向大面板测序数据（使用 MSK-IMPACT 测定），并在这些细胞系中对假设赋予 AR 的基因改变进行了建模。 75 名 ROS1 融合患者中有 8 名同时发生 MAPK 通路改变，这与较短的总生存期相关。此外，ROS1融合的诱导刺激了MEK/ERK信号的激活，而对AKT信号的影响最小，这表明MAPK途径在驱动ROS1融合阳性癌症中的重要性。在 8 名患者中，2 名患者在 ROS1 TKI 后获得的 MEK1 (MEK1delE41_L54) 和 MEKK1 (MEKK1delH907_C916) 中存在新的框内缺失，2 名患者存在 NF1 功能丧失突变。 ROS1 融合阳性细胞中 MEK1del 或 MEKK1del 的表达以及 NF1 的敲低激活了 MEK/ERK 信号传导并赋予了对 ROS1 TKI 的耐药性。 ROS1 和 MEK 的联合靶向抑制了表达 ROS1 融合和 MEK1del 的细胞的生长。我们证明 MAPK 通路的下游激活可以介导对 ROS1 TKI 的先天获得性耐药，并且携带 ROS1 融合和并发下游 MAPK 通路改变的患者生存率较差。我们的研究结果提出了针对这两种畸变的治疗策略。
ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes. ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9–mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines. Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del. We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.