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. 2025 Aug 11;43(8):1530-1548.e9.
doi: 10.1016/j.ccell.2025.06.011. Epub 2025 Jul 10.

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

Ana Galan-Cobo  1 , Natalie I Vokes  1 , Yu Qian  1 , David Molkentine  1 , Kavya Ramkumar  1 , Alvaro G Paula  1 , Marlese Pisegna  1 , Daniel J McGrail  2 , Alissa Poteete  1 , Sungnam Cho  1 , Minh Truong Do  1 , Amirali Karimi  1 , Yifan Kong  1 , Anisha Solanki  3 , Ankur Karmokar  3 , Nicolas Floc'h  3 , Adina Hughes  3 , Rebecca Sargeant  4 , Lucy Young  3 , Li Shen  5 , Gozde Kar  3 , Caezaan Keshvani  6 , Claudio Arrechedera  7 , Sharia Hernandez  7 , Katharina Schlacher  6 , Jing Wang  5 , Sonia Iyer  8 , James Conway  9 , Mohamed Reda Keddar  10 , Marta Milo  10 , Ilario de Toma  11 , Susan E Critchlow  3 , J Carl Barrett  8 , Jan Cosaert  3 , Alan Lau  3 , Viia Valge-Archer  3 , Lauren A Byers  1 , Simon T Barry  3 , John V Heymach  12
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Free article

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

Ana Galan-Cobo et al. Cancer Cell. .
Free article

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: ATR inhibition; DDR; KEAP1; LKB1; NSCLC; STK11; ceralasertib; immunotherapy; lung cancer.

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Conflict of interest statement

Declaration of interests J.V.H. reports receiving research support from AstraZeneca, Spectrum Pharmaceuticals, and Boehringer Ingelheim and has served on advisory committees for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, EMD Serono, Foundation Medicine, Hengrui Therapeutics, Genentech, GSK, Guardant Health, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Spectrum, Takeda, and receives royalties and licensing fees from Spectrum. L.A.B. reports receiving research support from AstraZeneca, Amgen, and Circle Pharma, and has served on advisory committees for AstraZeneca, Merck, Arrowhead Pharmaceuticals, Chugai Pharmaceutical, Genetech, BeiGene, AbbVie, Jazz, Puma Biotechnology, Amgen, Daiichi Sankyo, and Novartis. A.S., A.K., N.F., A.H., R.S., L.Y., G.K., A.L., V.V.-A., S.I., J.C., M.M., I.d.T., M.R.K., J.C.B., J.C., S.E.C., and S.T.B. are current AstraZeneca employees and share holders. The remaining authors have declared that no conflict of interest exists.

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