KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant non-small cell lung cancer
Ana Galán‐Cobo, Natalie I. Vokes, Yu Qian, David Molkentine, Kavya Ramkumar, Alvaro Guimaraes Paula, Marlese A. Pisegna, Daniel J. McGrail, Alissa Poteete, Sung-Nam Cho, Minh Truong, Amirali Karimi, Yifan Kong, Anisha Solanki, Ankur Karmokar, Nicolas Floc’h, Adina Hughes, Rebecca Sargeant, Lucy A. Young, Li Shen, Gozde Kar, Caezaan Keshvani, Claudio J. 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
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.