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A Multikinase Inhibitor AX-0085 Blocks FGFR1 Activation to Overcomes Osimertinib Resistance in Non-Small Cell Lung

Byung-Ho Rhie1,2, Janardhan Keshav Karapurkar3, Hyun-Yi Kim4

  • 1Institute of Medical Science, Kangwon National University, Chuncheon 24341, Republic of Korea.

Biomedicines
|January 28, 2026
PubMed

Insights

AX-0085, a dual inhibitor of AXL and FGFR1, effectively overcomes resistance to osimertinib in non-small cell lung cancer (NSCLC) by blocking key signaling pathways. This offers a promising new therapeutic strategy for patients with resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a frontline treatment for advanced non-small cell lung cancer (NSCLC) with EGFR-activating mutations.
  • Tumor recurrence due to acquired resistance to osimertinib is a significant clinical challenge in NSCLC treatment.
  • Activation of AXL (a neuroplastin) or FGFR1 (fibroblast growth factor receptor 1) are identified as major drivers of osimertinib resistance in NSCLC.

Purpose of the Study:

  • To investigate the therapeutic potential of AX-0085, a novel agent targeting both AXL and FGFR1, in overcoming osimertinib resistance in NSCLC.
  • To elucidate the molecular mechanisms by which AX-0085 impacts osimertinib-resistant NSCLC cells.

Main Methods:

  • Generation of osimertinib-resistant NSCLC cell lines harboring EGFR mutations in vitro.
  • Treatment of resistant cell lines with AX-0085.
  • Transcriptomic analyses to assess gene expression changes and signaling pathway alterations.
  • Assessment of AX-0085's effects on AXL and FGFR1 activation, cell proliferation, clonogenicity, and migration.

Main Results:

  • AX-0085 treatment altered the expression of genes involved in MAPK, ERK, and FGF receptor signaling pathways in osimertinib-resistant cells.
  • AX-0085 effectively inhibited AXL and FGFR1 activation, resensitizing resistant cells to osimertinib.
  • AX-0085 demonstrated potent inhibition of AXL and FGFR1-dependent oncogenic processes, including cell proliferation, clonogenicity, and migration.

Conclusions:

  • Dual inhibition of AXL and FGFR1 by AX-0085 represents a viable strategy to overcome acquired osimertinib resistance in NSCLC.
  • AX-0085 shows significant therapeutic potential for treating patients with osimertinib-resistant NSCLC tumors.
Keywords:
AX-0085AXLFGFR1NSCLCosimertinib resistance

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