肺腺鳞癌转分化驱动KRAS靶向治疗耐药  

Adeno-to-Squamous Transition Leads to Resistance to KRAS Inhibitorin Lung Cancer

作　　者：童欣媛 薛云 张宁霞 季红斌 TONG Xinyuan;XUE Yun;ZHANG Ningxia;JI Hongbin(Key Laboratory of Multi-Cell Systems,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,University of Chinese Academy of Sciences,Shanghai 200031,China)

机构地区：[1]多细胞体系结构与功能重点实验室,中国科学院分子细胞科学卓越创新中心/中国科学院上海生物化学与细胞生物学研究所,中国科学院大学,上海200031

出　　处：《中国细胞生物学学报》2024年第7期1317-1322,共6页Chinese Journal of Cell Biology

基　　金：国家重点研发计划(批准号:2022YFA1103900,2020YFA0803300);国家自然科学基金(批准号:32100593)资助的课题。

摘　　要：KRAS^(G12C)抑制剂(Adagrasib和Sotorasib)在靶向治疗KRAS^(G12C)突变的肺癌中已显示出较好的临床效果,然而耐药现象普遍存在。因此,探究KRAS抑制剂耐药机制极为重要。丝氨酸–苏氨酸激酶11(STK11)/LKB1通常在人肺腺癌中与KRAS共突变,KRAS/LKB1突变亚群对标准治疗响应较差。该研究发现治疗前已富集鳞癌特征的KRAS^(G12C)肺腺癌患者具有较短的Adagrasib治疗持续时间,且这一相关性在STK11/LKB1共突变的亚群中尤为显著。通过建立KRAS抑制剂耐药小鼠模型和腺鳞癌转分化类器官模型,该研究证明KRAS/LKB1突变的肿瘤细胞可以通过腺鳞癌转分化驱动KRAS抑制剂耐药。机制上,Elf5-ΔNp63转录轴可以调控腺鳞癌转分化过程并影响肿瘤细胞对KRAS抑制剂的药物响应。值得注意的是,在腺鳞癌转分化过渡状态中高表达的KRT6A基因与较差的Adagrasib响应显著相关。该研究揭示了肺腺鳞癌转分化是驱动KRAS抑制剂耐药的重要机制,且KRT6A有望成为新的生物学标志物预测患者对KRAS靶向治疗用药的响应。KRAS^(G12C) inhibitors,including Adagrasib and Sotorasib,have shown clinical efficacy in target-ing KRAS^(G12C)-mutated lung cancers.However,most patients develop resistance to these therapies,and it is impor-tant to explore the mechanism of KRAS inhibitor resistance.STK11(serine/threonine kinase 11)/LKB1 is frequently co-mutated with KRAS in non-small cell lung cancer.Loss of tumor suppressor gene LKB1 decreases sensitivity to drug treatment.In KRAS/LKB1 mutant lung adenocarcinoma(ADC)patients treated with Adagrasib monotherapy(KRYSTAL-1),enrichment for a squamous gene signature in the pre-treatment biopsy is significantly correlated with shorter treatment duration.Furthermore,integrative analysis of KCL(KRASLSL-G12C/+;Lkb1flox/flox)mouse model and KDL(KrasLSL-G12D/+;Lkb1flox/flox)organoid model of lung cancer demonstrates that AST(adeno-to-squamous tran-sition)is a prominent mechanism of acquired resistance to KRAS inhibition.The transcriptomic and epigenomic analyses further reveal that Elf5-ΔNp63 axis regulates AST and modulates response to KRAS inhibition.Important-ly,high expression of KRT6A in high-plasticity cell state during AST is associated with poor Adagrasib response.Taken together,the study demonstrates that AST is one of the mechanisms of KRAS inhibitor resistance and pro-vides potential biomarkers for KRAS-targeted therapies in lung cancer.

关 键 词：腺鳞癌转分化 KRAS抑制剂 LKB1 KRT6A 

分 类 号：R734.2[医药卫生—肿瘤]