Notch pathway regulates osimertinib drug-tolerant persistence in EGFR-mutated non-small-cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Osimertinib, a third-generation EGFR-TKI, shows efficacy in EGFR-mutated NSCLC but is limited by acquired resistance.
• Drug-tolerant persister (DTP) cells, characterized by reduced sensitivity and non-genetic resistance, contribute to treatment failure.
• The Notch pathway is implicated in tumorigenesis and resistance to prior EGFR-TKIs, but its role in osimertinib resistance remains unclear.

Purpose of the Study:

• To investigate the involvement of the Notch pathway in osimertinib resistance in EGFR-mutated non-small-cell lung cancer (NSCLC).
• To evaluate the therapeutic potential of combining a Notch inhibitor with osimertinib.

Main Methods:

• Analysis of NOTCH1 and Notch target gene expression in osimertinib DTP cells.
• In vitro and in vivo studies using a γ-secretase inhibitor (GSI) to block Notch signaling.
• Assessment of phospho-ERK and DUSP1 expression in response to combined GSI and osimertinib treatment.
• Examination of Notch1 and HES1 expression in human NSCLC tumor tissues post-EGFR-TKI treatment.

Main Results:

• NOTCH1 and Notch target genes were upregulated in osimertinib DTP cells.
• Inhibition of Notch signaling with GSI reduced drug-tolerant persistence both in vitro and in vivo.
• Combined GSI and osimertinib suppressed phospho-ERK, partly through enhanced DUSP1 expression.
• Notch1 and HES1 upregulation was observed in approximately half of human EGFR-mutated NSCLC tumors after EGFR-TKI treatment.

Conclusions:

• The Notch pathway plays a significant role in mediating resistance to osimertinib in EGFR-mutated NSCLC.
• Combining a γ-secretase inhibitor (GSI) with osimertinib demonstrates potential as a therapeutic strategy to overcome osimertinib resistance.
• This combination therapy may offer a new treatment option for patients with EGFR-mutated NSCLC who develop resistance to osimertinib.