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

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; Gozde Kar; Caezaan Keshvani; Claudio Arrechedera; Sharia Hernandez; Katharina Schlacher; Jing Wang; Sonia Iyer; James Conway; Mohamed Reda Keddar; Marta Milo; Ilario de Toma; Susan E Critchlow; J Carl Barrett; Jan Cosaert; Alan Lau; Viia Valge-Archer; Lauren A Byers; Simon T Barry; John V Heymach

doi:10.1016/j.ccell.2025.06.011

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

Cancer Cell. 2025 Jul 5:S1535-6108(25)00261-2. doi: 10.1016/j.ccell.2025.06.011. Online ahead of print.

Authors

Ana Galan-Cobo¹, Natalie I Vokes¹, Yu Qian¹, David Molkentine¹, Kavya Ramkumar¹, Alvaro G Paula¹, Marlese Pisegna¹, Daniel J McGrail², Alissa Poteete¹, Sungnam Cho¹, Minh Truong Do¹, Amirali Karimi¹, Yifan Kong¹, Anisha Solanki³, Ankur Karmokar³, Nicolas Floc'h³, Adina Hughes³, Rebecca Sargeant⁴, Lucy Young³, Li Shen⁵, Gozde Kar³, Caezaan Keshvani⁶, Claudio Arrechedera⁷, Sharia Hernandez⁷, Katharina Schlacher⁶, Jing Wang⁵, Sonia Iyer⁸, James Conway⁹, Mohamed Reda Keddar¹⁰, Marta Milo¹⁰, Ilario de Toma¹¹, Susan E Critchlow³, J Carl Barrett⁸, Jan Cosaert³, Alan Lau³, Viia Valge-Archer³, Lauren A Byers¹, Simon T Barry³, John V Heymach¹²

Affiliations

¹ Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.
³ Early Oncology R&D, AstraZeneca, Cambridge, UK.
⁴ Imaging Sciences, CPSS, AstraZeneca, Cambridge, UK.
⁵ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.
⁹ Oncology Data Science, Oncology R&D, AstraZeneca, Gaithersburg, MD, USA.
¹⁰ Oncology Data Science, Oncology R&D, AstraZeneca, Cambridge, UK.
¹¹ Early Oncology, Oncology R&D, AstraZeneca, Barcelona, Spain.
¹² Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jheymach@mdanderson.org.

PMID: 40645185
DOI: 10.1016/j.ccell.2025.06.011

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.