Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with Ointment.

For cutaneous squamous cell carcinoma (cSCC), topical treatment is an essential option for patients who are not candidates for, or who refuse, surgery. Epidermal growth factor receptor (EGFR) plays a key role in the development of cSCC, but EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have shown only partial clinical benefit in this disease. Thus, there is an unmet need to develop novel strategies for improving the efficacy of TKIs in cSCC. We previously demonstrated that the tumor-suppressive microRNA (miRNA) functions as a negative modulator of the cytoprotective cancer cell survival processes and is a useful anticancer therapeutic agent. In the present study, we found that topical application of an ointment containing inhibited tumor growth without toxicity in a cSCC xenograft mouse model and a 7,12-dimethylbenz[]anthracene (DMBA)/12--tetradecanoylphorbol-13-acetate (TPA)-induced papilloma mouse model. Functional validation revealed that overexpression reduced glutaminolysis by directly targeting , a glutamine transporter. Furthermore, overexpression of synergistically enhanced TKI-induced cytotoxicity by triggering severe energetic stress and . Thus, we propose that topical treatment with ointment is a useful strategy for improving for EGFR TKI-based therapy for cSCC.