中国科学院分子细胞科学卓越创新中心季红斌等研究人员发现，腺癌向鳞癌转化促使LKB1突变肺癌对KRAS抑制产生耐药性。相关论文于2024年2月22日在线发表在《癌细胞》杂志上。

在KRAS^G12C和STK11/LKB1共突变的肺腺癌患者中，研究人员发现治疗前活检中鳞癌基因特征的富集与adagrasib的不良反应相关。对Lkb1基因缺陷的KRAS^G12C和Kras^G12D肺癌小鼠模型以及接受KRAS抑制剂治疗的类器官的研究显示，肿瘤会启动一种谱系可塑性程序，即腺癌向鳞癌转化（AST），从而对KRAS抑制剂产生抗性。转录组学和表观基因组学分析显示ΔNp63驱动AST并调节对KRAS抑制的反应。

研究人员发现了以AST可塑性特征和Krt6a的表达为标志的中间高可塑性细胞状态。值得注意的是，AST可塑性特征和KRT6A的基线表达与adagrasib的不良反应相关。这些数据表明了AST在KRAS抑制剂耐药性中的作用，并为肺癌KRAS靶向疗法提供了预测性生物标记物。

据了解，KRAS^G12C抑制剂（adagrasib和sotorasib）在靶向KRAS^G12C突变肺癌方面已显示出临床前景；然而，大多数患者最终会产生耐药性。

附：英文原文

Title: Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer

Author: Xinyuan Tong, Ayushi S. Patel, Eejung Kim, Hongjun Li, Yueqing Chen, Shuai Li, Shengwu Liu, Julien Dilly, Kevin S. Kapner, Ningxia Zhang, Yun Xue, Laura Hover, Suman Mukhopadhyay, Fiona Sherman, Khrystyna Myndzar, Priyanka Sahu, Yijun Gao, Fei Li, Fuming Li, Zhaoyuan Fang, Yujuan Jin, Juntao Gao, Minglei Shi, Satrajit Sinha, Luonan Chen, Yang Chen, Thian Kheoh, Wenjing Yang, Itai Yanai, Andre L. Moreira, Vamsidhar Velcheti, Benjamin G. Neel, Liang Hu, James G. Christensen, Peter Olson, Dong Gao, Michael Q. Zhang, Andrew J. Aguirre, Kwok-Kin Wong, Hongbin Ji

Issue&Volume: 2024-02-22

Abstract: KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

DOI: 10.1016/j.ccell.2024.01.012

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00036-9