KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant non-small cell lung cancer

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-07-10 DOI:10.1016/j.ccell.2025.06.011

Ana Galan-Cobo, Natalie I. Vokes, Yu Qian, David Molkentine, Kavya Ramkumar, Alvaro G. Paula, Marlese Pisegna, Daniel J. McGrail, Alissa Poteete, Sungnam Cho, Minh Truong Do, Amirali Karimi, Yifan Kong, Anisha Solanki, Ankur Karmokar, Nicolas Floc’h, Adina Hughes, Rebecca Sargeant, Lucy Young, Li Shen, John V. Heymach

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引用次数: 0

Abstract

KRAS mutations frequently co-occur with alterations in STK11/LKB1 and/or KEAP1, defining an aggressive subset of lung cancers resistant to immuno- and chemotherapy. While LKB1 loss is associated with vulnerability to DNA damage response-based therapies, the impact of KEAP1 alterations remains unknown. We demonstrate that KEAP1-NRF2 pathway drives a compensatory modulation of ATR-CHK1 signaling, enhancing vulnerability to ATR inhibitors (ATRi), particularly in the setting of increased replication stress associated with LKB1 loss. ATRi shows enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient non-small cell lung cancer (NSCLC) models and synergizes with gemcitabine. ATRi also enhances antitumor immunity and mitigates the immunosuppressed phenotype of LKB1/KEAP1-deficient tumors. In the HUDSON trial, LKB1/KEAP1-deficient NSCLC patients demonstrate enhanced benefits to the ATRi ceralasertib plus durvalumab. These findings suggest that alterations in the KEAP1-NRF2 pathway and/or LKB1 are associated with enhanced sensitivity to ATRi and could serve as biomarkers for predicting response to ATRi combination regimens.

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KEAP1和STK11/LKB1的改变增强了KRAS突变型非小细胞肺癌对ATR抑制的易感性

KRAS突变经常与STK11/LKB1和/或KEAP1的改变共同发生，定义了对免疫和化疗耐药的肺癌的侵袭性亚群。虽然LKB1缺失与DNA损伤反应疗法的易感性相关，但KEAP1改变的影响仍不清楚。我们证明KEAP1-NRF2通路驱动ATR- chk1信号的代偿性调节，增强对ATR抑制剂（ATRi）的易感性，特别是在与LKB1丢失相关的复制应激增加的情况下。ATRi在LKB1和/或keap1缺陷的非小细胞肺癌（NSCLC）模型中显示出增强的抗肿瘤活性，并与吉西他滨协同作用。ATRi还能增强抗肿瘤免疫，减轻LKB1/ keap1缺陷肿瘤的免疫抑制表型。在HUDSON试验中，LKB1/ keap1缺陷NSCLC患者显示出ATRi ceralasertib + durvalumab的益处增强。这些发现表明，KEAP1-NRF2通路和/或LKB1的改变与对ATRi的敏感性增强有关，可以作为预测对ATRi联合方案反应的生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.