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

Ana Galan-Cobo1, Natalie I Vokes1, Yu Qian1

  • 1Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cancer Cell
|July 11, 2025
PubMed

Insights

Loss of LKB1 or KEAP1 in lung cancer creates vulnerabilities. ATR inhibitors show promise, enhancing chemotherapy and immunotherapy, especially in combination treatments for non-small cell lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • KRAS mutations in lung cancer often co-occur with STK11/LKB1 or KEAP1 alterations, leading to aggressive disease resistant to standard therapies.
  • LKB1 loss is linked to DNA damage response vulnerabilities, but the role of KEAP1 alterations in therapeutic response is unclear.
  • The KEAP1-NRF2 pathway's function in compensatory signaling and its impact on treatment sensitivity require further investigation.

Purpose of the Study:

  • To investigate the impact of KEAP1 alterations on therapeutic vulnerabilities in lung cancer.
  • To determine the efficacy of ATR inhibitors (ATRi) in LKB1 and/or KEAP1-deficient non-small cell lung cancer (NSCLC).
  • To evaluate the potential of ATRi as a biomarker for predicting treatment response in specific NSCLC subsets.

Main Methods:

  • Demonstrated KEAP1-NRF2 pathway's role in modulating ATR-CHK1 signaling.
  • Assessed ATRi anti-tumor activity and synergy with gemcitabine in LKB1/KEAP1-deficient NSCLC models.
  • Analyzed effects of ATRi on antitumor immunity and immunosuppression in deficient tumors.
  • Examined patient outcomes in the HUDSON trial for LKB1/KEAP1-deficient NSCLC treated with ceralasertib plus durvalumab.

Main Results:

  • KEAP1-NRF2 pathway activation enhances vulnerability to ATR inhibitors, particularly with concurrent LKB1 loss and replication stress.
  • ATRi demonstrated significant anti-tumor activity and synergistic effects with gemcitabine in preclinical models of LKB1/KEAP1-deficient NSCLC.
  • ATRi treatment improved antitumor immunity and reversed immunosuppression in LKB1/KEAP1-deficient tumors.
  • LKB1/KEAP1-deficient NSCLC patients in the HUDSON trial showed improved outcomes with ceralasertib and durvalumab.

Conclusions:

  • Alterations in the KEAP1-NRF2 pathway and/or LKB1 are associated with heightened sensitivity to ATR inhibitors.
  • ATRi combination regimens show promise for treating aggressive NSCLC subsets with LKB1/KEAP1 deficiencies.
  • KEAP1 and LKB1 status can serve as predictive biomarkers for response to ATRi-based therapies in NSCLC.
Keywords:
ATR inhibitionDDRKEAP1LKB1NSCLCSTK11ceralasertibimmunotherapylung cancer

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