M1C 是对 KRAS 抑制剂耐药的 NSCLC KRAS G12C 突变肿瘤的可成药靶标

M1C is a druggable target for NSCLC KRAS G12C mutant tumors resistant to KRAS inhibitors.

期刊: Oncogene
PMID: 42557306
原文: PubMed ↗
发布日期: 2026-08-06

作者

Shinkichi Takamori — Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Naoki Haratake — Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Atrayee Bhattacharya — Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Hiroki Ozawa — Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Keisuke Shigeta — Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Mai Onishi — Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Kentaro Nonaka — Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Takefumi Komiya — Division of Hematology and Oncology Penn State College of Medicine, Hershey, PA, USA.
Hiroki Komatsuda — Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Tomoyoshi Takenaka — Department of Surgery and Science Graduate School of Medical Sciences Kyushu University, Fukuoka, Japan.
Tomoharu Yoshizumi — Department of Surgery and Science Graduate School of Medical Sciences Kyushu University, Fukuoka, Japan.
Chendi Li — Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Jiehui Deng — Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
Aaron N Hata — Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Kwok K Wong — Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
Mark D Long — Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Donald Kufe — Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA. Donald_Kufe@dfci.harvard.edu.

作者单位

Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Division of Hematology and Oncology Penn State College of Medicine, Hershey, PA, USA.
Department of Surgery and Science Graduate School of Medical Sciences Kyushu University, Fukuoka, Japan.
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA. Donald_Kufe@dfci.harvard.edu.

摘要

中文

使用等位基因选择性 sotorasib 和 adagrasib 抑制剂治疗 NSCLC KRAS G12C 突变肿瘤总是与获得性耐药相关。MUC1 编码的致癌 M1C 蛋白是 NSCLC KRAS 突变细胞自我更新所必需的。我们报告，用 sotorasib 处理 NSCLC KRAS G12C 细胞通过 STAT1 依赖性途径诱导 M1C 表达。反过来，M1C 通过 NF-κB 介导的上皮-间质转化（EMT）和粘液样基因程序诱导驱动 sotorasib 耐药表型。靶向 M1C→NF-κB 信号（i）抑制 EMT 和粘蛋白基因，（ii）逆转 sotorasib 耐药。具有转化相关性的是，使用 M1C 抗体-药物偶联物（ADC）治疗对两种 sotorasib 耐药的 NSCLC KRAS G12C 细胞系和两种患者来源的肿瘤异种移植模型有效。对接受 sotorasib/adagrasib 治疗且过表达 MUC1 的 NSCLC KRAS G12C 肿瘤患者的分析与总生存期降低相关。这些发现确定 M1C 是 sotorasib 耐药的关键效应器，也是治疗难治性 NSCLC KRAS G12C 突变肿瘤患者的靶点。

English

Treatment of NSCLC KRAS G12C mutant tumors with the allele-selective sotorasib and adagrasib inhibitors is invariably associated with acquired resistance. The MUC1-encoded oncogenic M1C protein is necessary for self-renewal of NSCLC KRAS mutant cells. We report that treatment of NSCLC KRAS G12C cells with sotorasib induces M1C expression by a STAT1-dependent pathway. In turn, M1C drives the sotorasib resistant phenotype by NF-κB-mediated induction of the epithelial-mesenchymal transition (EMT) and a mucinous gene program. Targeting M1C→NF-κB signaling (i) suppresses EMT and mucin genes, and (ii) reverses sotorasib resistance. Of translational relevance, treatment with a M1C antibody-drug conjugate (ADC) is effective against two sotorasib-resistant NSCLC KRAS G12C cell lines and two patient-derived tumor xenograft models. Analysis of patients with NSCLC KRAS G12C tumors treated with sotorasib/adagrasib and overexpressing MUC1 associates with decreases in overall survival. These findings identify M1C as a key effector of sotorasib resistance and as a target for treatment of patients with refractory NSCLC KRAS G12C mutant tumors.

分类与指标

研究类型: 基础研究
病种: 肺癌
JCR 分区: Q1
影响因子: 9.1
新锐分区: 1区