Epidermal growth
factor receptor (EGFR)-targeted therapy has been
proven vital in the last two decades for the treatment of multiple
cancer types, including nonsmall cell lung cancer, glioblastoma,
breast cancer and head and neck squamous cell carcinoma. Unfortunately,
the majority of approved EGFR inhibitors fall into the drug resistance
category because of continuous mutations and acquired resistance.
Recently, autophagy has surfaced as one of the emerging underlying
mechanisms behind resistance to EGFR-tyrosine kinase inhibitors (TKIs).
Previously, we developed a series of 4″-alkyl EGCG (4″-Cn EGCG, n = 6, 8, 10, 12,
14, 16, and 18) derivatives with enhanced anticancer effects and stability.
Therefore, the current study hypothesized that 4″-alkyl EGCG
might induce cytoprotective autophagy upon EGFR inhibition, and inhibition
of autophagy may lead to improved cytotoxicity. In this study, we
have observed growth inhibition and caspase-3-dependent apoptosis
in 4″-alkyl EGCG derivative-treated glioblastoma cells (U87-MG).
We also confirmed that 4″-alkyl EGCG could inhibit EGFR in
the cells, as well as mutant L858R/T790M EGFR, through an in vitro
kinase assay. Furthermore, we have found that EGFR inhibition with
4″-alkyl EGCG induces cytoprotective autophagic responses,
accompanied by the blockage of the AKT/mTOR signaling pathway. In
addition, cytotoxicity caused by 4″-C10 EGCG, 4″-C12 EGCG, and 4″-C14 EGCG was significantly
increased after the inhibition of autophagy by the pharmacological
inhibitor chloroquine. These findings enhance our understanding of
the autophagic response toward EGFR inhibitors in glioblastoma cells
and suggest a potent combinatorial strategy to increase the therapeutic
effectiveness of EGFR-TKIs.