Broad-spectrum Cross-resistance to Anticancer Drugs Mediated by Epidermal Growth Factor Receptor

Background: The oncogenic role of epidermal growth factor receptor (EGFR) has been intensively studied. However, its emerging role in drug resistance has not been fully addressed. Materials and Methods: This study systematically investigated the correlation of mRNA and protein expression of EGFR, as well as gene amplification and mutations with the log-transformed half-maximal inhibitory concentration (log₁₀IC₅₀) values obtained from the NCI panel of 60 human tumor cell lines against 83 standard anticancer agents and the top 10 natural cytotoxic products previously screened by us. Results: EGFR protein expression, rather than other measurements, was most frequently associated with drug response. Log₁₀IC₅₀ and EGFR protein level were significantly positively correlated under all investigated DNA topoisomerase (TOPO) II inhibitors, followed by 81% of alkylating agents and platinum-based compounds, 71% of anti-hormones, 66% of TOPO I inhibitors and 50% of antibiotics. Furthermore, 60% of cytotoxic natural products did not reveal significant correlations. Conclusion: Collectively, we showed a broad-spectrum of cross-resistance towards clinical drugs mediated by EGFR. Natural cytotoxic products may be further developed as novel drugs to overcome EGFR-associated resistance to clinically established anticancer drugs.