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AKR1C3 Inhibition: A Strategy to Reverse Osimertinib Resistance in Non-small Cell Lung Cancer

Wei Li1

  • 1State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.

Journal of Medicinal Chemistry
|March 13, 2026
PubMed

Insights

Osimertinib resistance in non-small cell lung cancer (NSCLC) due to the EGFR C797S mutation can be overcome. Combining Osimertinib with SG-55, an AKR1C3 inhibitor, restores sensitivity in NSCLC cells with this mutation.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Non-small cell lung cancer (NSCLC) treatment faces challenges with Osimertinib resistance.
  • The EGFR C797S mutation is a key mechanism driving Osimertinib resistance in NSCLC.
  • Developing strategies to overcome this resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the efficacy of combining Osimertinib with SG-55, a novel AKR1C3 inhibitor, in overcoming Osimertinib resistance.
  • To evaluate the potential of targeting AKR1C3 to restore sensitivity in NSCLC cells with the EGFR C797S mutation.
  • To explore AKR1C3 inhibition as a therapeutic strategy against drug-resistant NSCLC.

Main Methods:

  • Utilized NSCLC cell lines harboring the EGFR C797S mutation.
  • Administered a combination therapy of Osimertinib and SG-55.
  • Assessed the restoration of sensitivity to Osimertinib in treated cells.

Main Results:

  • The combination of Osimertinib and SG-55 effectively reversed Osimertinib resistance in NSCLC cells with the C797S mutation.
  • Sensitivity to Osimertinib was restored in the resistant NSCLC cells.
  • SG-55 demonstrated potent selective inhibition of AKR1C3.

Conclusions:

  • AKR1C3 inhibition is a promising strategy for overcoming Osimertinib resistance in NSCLC.
  • The combination of Osimertinib and SG-55 shows potential for preclinical development.
  • Targeting AKR1C3 represents a novel approach to combatting antitumor drug resistance in NSCLC.

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