Blocking ROR1 enhances the roles of erlotinib in lung adenocarcinoma cell lines

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Non-small cell lung cancer (NSCLC) treatment advances with tyrosine kinase inhibitors (TKIs) but faces resistance challenges.
• Receptor tyrosine kinase-like orphan receptor 1 (ROR1) interacts with epidermal growth factor receptor (EGFR) and sustains EGFR-ERBB3-PI3K signaling.
• Previous studies linked ROR1 inhibition to reduced AKT/mammalian target of rapamycin (mTOR) signaling, increased apoptosis, and decreased proliferation in lung adenocarcinoma.

Purpose of the Study:

• To investigate if inhibiting ROR1 can prevent or overcome erlotinib resistance in NSCLC cell lines.
• To evaluate the effect of ROR1 inhibition on the AKT/mTOR signaling pathway in TKI-resistant NSCLC cells.

Main Methods:

• Utilized erlotinib-resistant NSCLC cell lines (XLA-07, NCI-H1975) and an acquired-resistant cell line (PC-9erlo).
• Employed small interfering RNA (siRNA) to inhibit ROR1 expression.
• Assessed the impact of ROR1 inhibition on erlotinib's anti-proliferative and apoptosis-inducing effects.
• Analyzed the activity of key molecules in the AKT/mTOR signaling pathway (GSK-3α/β, PTEN, AKT, mTOR, p70S6K).

Main Results:

• Inhibition of ROR1 using siRNA significantly enhanced the anti-proliferative and apoptosis-inducing effects of erlotinib in TKI-resistant NSCLC cells.
• ROR1 inhibition modulated the activity of key signaling molecules within the AKT/mTOR pathway, including GSK-3α/β, PTEN, AKT, mTOR, and p70S6K.
• These findings were consistent across different erlotinib-resistant NSCLC models.

Conclusions:

• Targeting ROR1 represents a promising therapeutic strategy for ROR1-positive NSCLC.
• ROR1 inhibition is particularly effective in overcoming acquired resistance to epidermal growth factor receptor TKIs (EGFR-TKIs).
• This approach offers a potential new avenue for treating patients with refractory or resistant NSCLC.