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BMX inhibition overcomes small cell lung cancer chemoresistance by stabilizing E2F1 via ERK1/2-Cyclin D1/CDK4/6 axis

Ting Wu1,2, Shuang Qi1,3,4, Chenliang Shi1,2

  • 1Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.

Signal Transduction and Targeted Therapy
|April 7, 2026
PubMed

Insights

The BMX-E2F1 axis drives chemotherapy resistance in small cell lung cancer (SCLC). Targeting this axis with BMX inhibitors like IHMT-15137 can overcome resistance and improve SCLC treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Chemotherapy resistance is a major obstacle in treating small cell lung cancer (SCLC).
  • Understanding the molecular mechanisms of chemoresistance is crucial for developing effective therapies.
  • The bone marrow tyrosine kinase on chromosome X (BMX)-E2F transcription factor 1 (E2F1) axis has emerged as a potential regulator.

Purpose of the Study:

  • To elucidate the role of the BMX-E2F1 axis in SCLC chemotherapy resistance.
  • To identify potential therapeutic targets and strategies to overcome chemoresistance in SCLC.

Main Methods:

  • Investigated the expression and interaction of BMX and E2F1 in SCLC tissues and cells.
  • Utilized molecular biology techniques including gene knockdown, Western blotting, and signaling pathway analysis.
  • Evaluated the efficacy of a novel BMX inhibitor (IHMT-15137) in combination with cisplatin using in vitro (patient-derived cells/organoids) and in vivo (xenograft) models.

Main Results:

  • Synchronous upregulation of phosphorylated BMX and E2F1 was observed in chemoresistant SCLC.
  • BMX stabilizes E2F1 through the ERK1/2-Cyclin D1/CDK4/6 pathway, inhibiting its degradation and promoting chemoresistance.
  • Inhibition of BMX reversed chemoresistance, sensitized cells to cisplatin, and reduced tumor growth in vivo.
  • The combination of IHMT-15137 and cisplatin demonstrated synergistic anti-tumor effects with minimal toxicity.

Conclusions:

  • The BMX-E2F1 axis is a key driver of chemotherapy resistance in SCLC.
  • Targeting the BMX-E2F1 axis, particularly with BMX inhibitors, represents a promising therapeutic strategy to enhance SCLC treatment outcomes.
  • IHMT-15137 in combination with cisplatin offers a potential novel therapeutic approach for overcoming SCLC chemoresistance.

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