Faculty, Staff and Student Publications

Publication Date

8-11-2025

Journal

Cancer Cell

DOI

10.1016/j.ccell.2025.06.011

PMID

40645185

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.

Keywords

Kelch-Like ECH-Associated Protein 1, Carcinoma, Non-Small-Cell Lung, Protein Serine-Threonine Kinases, Humans, Lung Neoplasms, Proto-Oncogene Proteins p21(ras), AMP-Activated Protein Kinase Kinases, Ataxia Telangiectasia Mutated Proteins, Animals, Mice, Mutation, NF-E2-Related Factor 2, Cell Line, Tumor, Signal Transduction, Xenograft Model Antitumor Assays, Deoxycytidine, Protein Kinase Inhibitors, Antineoplastic Combined Chemotherapy Protocols, Gemcitabine

Published Open-Access

yes

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