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ER-851, a Novel Selective Inhibitor of AXL, Overcomes Resistance to Antimitotic Drugs

Shuntaro Tsukamoto1, Naoko Hata Sugi1, Kyoko Nishibata1

  • 1Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan.

Molecular Cancer Therapeutics
|October 24, 2022
PubMed

Insights

A novel small molecule, ER-851, effectively inhibits AXL receptor tyrosine kinase, overcoming cancer therapy resistance. This potent and selective AXL inhibitor shows promise in preventing tumor relapse and enhancing survival in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cancer therapy resistance, particularly to antimitotic drugs, is a significant clinical challenge.
  • Tumor cell subpopulations expressing AXL (a receptor tyrosine kinase) are enriched post-treatment, leading to relapse.
  • Elevated AXL expression correlates with clinical drug resistance, highlighting its pivotal role.

Purpose of the Study:

  • To identify novel therapeutic strategies to overcome cancer drug resistance.
  • To investigate the role of AXL in mediating resistance to antimitotic therapies.
  • To evaluate the efficacy and safety of a novel AXL inhibitor, ER-851.

Main Methods:

  • Comprehensive gene expression analysis of chemoresistant tumor cells in human lung and triple-negative breast cancer xenograft models.
  • Evaluation of ER-851, a potent and selective AXL inhibitor, in combination with antimitotic drugs.
  • Assessment of antitumor effects and relapse-free survival in preclinical models.
  • Toxicological assessment, specifically for retinal toxicity.

Main Results:

  • ER-851 demonstrated potent and selective inhibition of AXL.
  • Combination treatment with ER-851 and antimitotic drugs showed significant antitumor effects and prolonged relapse-free survival in triple-negative breast cancer models.
  • ER-851 did not induce retinal toxicity in preclinical models, unlike some other inhibitors.

Conclusions:

  • AXL is a validated therapeutic target for overcoming resistance to antimitotic cancer therapies.
  • ER-851 is a promising drug candidate for treating AXL-expressing tumors resistant to antimitotic agents.
  • ER-851 offers a potential strategy to improve patient outcomes by overcoming acquired drug resistance.

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