ATR Inhibitor M6620 (VX-970) Enhances the Effect of Radiation in Non-Small Cell Lung Cancer Brain Metastasis Patient-Derived Xenografts.
ATR Inhibitor M6620 (VX-970) Enhances the Effect of Radiation in Non-Small Cell Lung Cancer Brain Metastasis Patient-Derived Xenografts.
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DOI：
10.1158/1535-7163.mct-21-0305
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发表时间：
2021-11
影响因子：
5.7
通讯作者：
Kimple RJ
中科院分区：
文献类型：
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作者：
Baschnagel AM;Elnaggar JH;VanBeek HJ;Kromke AC;Skiba JH;Kaushik S;Abel L;Clark PA;Longhurst CA;Nickel KP;Leal TA;Zhao SG;Kimple RJ
M6620 是一种 ATM 和 RAD3 相关 (ATR) 激酶的选择性 ATP 竞争性抑制剂，目前正在对非小细胞肺癌 (NSCLC) 脑转移患者的放射治疗进行研究。我们评估了 NSCLC 的 DNA 损伤反应 (DDR) 通路谱，并评估了 M6620 在临床前 NSCLC 脑转移模型中的放射增敏作用。对 NSCLC 患者样本进行 DDR 基因和通路的突变分析和转录组分析。通过增殖、克隆存活、细胞凋亡、细胞周期以及 DNA 损伤信号传导和修复测定来评估 NSCLC 细胞系。 NSCLC 脑转移患者来源的异种移植模型用于评估颅内反应和总体生存率。进行体内免疫组织化学以确认体外结果。很大一部分 NSCLC 患者肿瘤表现出 DDR 通路的富集。 DDR 通路与肺鳞状细胞组织学相关； ATR、ATM、BRCA1、BRCA2、CHEK1 和 CHEK2 的突变与肺腺癌中 DDR 通路的富集相关。 M6620 减少放射治疗后的集落形成，并导致 DNA DSB 修复的抑制、放射诱导的 G2 细胞检查点的废除以及功能失调的微核的形成，从而导致放射诱导的有丝分裂死亡增强。与单独放疗相比，M6620 和放疗的结合提高了小鼠的总体生存率。体内免疫组织化学显示放射加 M6620 组中 pChk1 受到抑制。 M6620 增强了我们的临床前 NSCLC 脑转移模型中的放疗效果，支持正在进行的临床试验 (NCT02589522)，该试验评估 M6620 与全脑放疗联合治疗 NSCLC 脑转移患者。
M6620, a selective ATP-competitive inhibitor of the ATM and RAD3-related (ATR) kinase, is currently under investigation with radiation in patients with non-small cell lung cancer (NSCLC) brain metastases. We evaluated the DNA damage response (DDR) pathway profile of NSCLC and assessed the radiosensitizing effects of M6620 in a preclinical NSCLC brain metastasis model. Mutation analysis and transcriptome profiling of DDR genes and pathways was performed on NSCLC patient samples. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, cell cycle, and DNA damage signaling and repair assays. NSCLC brain metastasis patient-derived xenograft models were used to assess intracranial response and overall survival. In vivo immunohistochemistry was performed to confirm in vitro results. A significant portion of NSCLC patient tumors demonstrated enrichment of DDR pathways. DDR pathways correlated with lung squamous cell histology; and mutations in ATR, ATM, BRCA1, BRCA2, CHEK1, and CHEK2 correlated with enrichment of DDR pathways in lung adenocarcinomas. M6620 reduced colony formation after radiotherapy and resulted in inhibition of DNA DSB repair, abrogation of the radiation-induced G2 cell checkpoint, and formation of dysfunctional micronuclei, leading to enhanced radiation-induced mitotic death. The combination of M6620 and radiation resulted in improved overall survival in mice compared to radiation alone. In vivo immunohistochemistry revealed inhibition of pChk1 in the radiation plus M6620 group. M6620 enhances the effect of radiation in our preclinical NSCLC brain metastasis models, supporting the ongoing clinical trial (NCT02589522) evaluating M6620 in combination with whole brain irradiation in patients with NSCLC brain metastases.