AXL/CDCP1/SRC axis confers acquired resistance to osimertinib in lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Osimertinib, a third-generation EGFR-TKI, is used for non-small cell lung cancer (NSCLC) with EGFR mutations.
• Acquired resistance to osimertinib remains a significant clinical challenge, limiting long-term treatment efficacy.

Purpose of the Study:

• To elucidate a novel mechanism of acquired resistance to osimertinib in NSCLC.
• To investigate potential strategies for overcoming osimertinib resistance.

Main Methods:

• Established osimertinib-resistant NSCLC cell lines with T790M mutation.
• Analyzed protein expression (EGFR family, MET, AXL, CDCP1, SRC) and AKT activation.
• Utilized gene silencing (CDCP1, AXL, SRC) and pharmacological inhibition (dasatinib).
• Examined refractory tumor samples from patients treated with osimertinib.

Main Results:

• Osimertinib resistance was associated with reduced EGFR/MET and increased AXL/CDCP1/SRC expression, alongside AKT activation.
• Osimertinib treatment induced AXL and CDCP1 expression over time.
• Silencing AXL or CDCP1 restored osimertinib sensitivity by reducing SRC/AKT activation.
• Inhibition of SRC or dasatinib suppressed AKT phosphorylation and cell growth.
• Increased AXL and CDCP1 expression was found in patient tumor samples resistant to osimertinib.

Conclusions:

• AXL/SRC/AKT and CDCP1/SRC/AKT signaling pathways contribute to acquired osimertinib resistance in NSCLC.
• Targeting AXL, CDCP1, or SRC may represent a viable strategy to overcome osimertinib resistance and improve clinical outcomes.