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

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.