Targeting PKCι-PAK1 in EGFR-mutation positive non-small cell lung cancer

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against EGFR-mutation positive non-small cell lung cancer (NSCLC).
• However, acquired resistance to EGFR TKIs leads to universal disease progression, necessitating alternative treatment strategies.

Purpose of the Study:

• To investigate the efficacy of auranofin, an anti-rheumatoid agent and selective oncogenic protein kinase C iota (PKCι) inhibitor, in combination with IPA-3, a p21-activated kinase 1 (PAK1) inhibitor.
• To evaluate this combination in both treatment-naïve and EGFR TKI-resistant EGFR-mutation positive NSCLC cell lines.

Main Methods:

• Utilized PC9 and HCC827 NSCLC cell lines, including four derived EGFR TKI-resistant lines.
• Performed cell viability assays, drug combination studies, and western blotting to assess drug effects.
• Calculated combination indexes and analyzed receptor tyrosine kinase (RTK) and non-RTK expression.

Main Results:

• The combination of IPA-3 and auranofin demonstrated high synergy in all tested cell lines, with combination indexes ranging from 0.37 to 0.62.
• This synergistic effect was associated with the abrogation of key signaling pathways, including EGFR, CDCP1, AXL, MET, and downstream effectors like PAK1, PKCι, ERK, AKT, STAT3, Src, and YAP1.

Conclusions:

• The combination of auranofin and IPA-3 presents a promising therapeutic approach for EGFR-mutation positive NSCLC.
• This drug combination could overcome resistance to existing EGFR TKIs, offering a potential new treatment solution for patients with advanced NSCLC.