Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with miR-634 Ointment

• Published in: Molecular therapy. Oncolytics Vol. 19; pp. 294 - 307
• Main Authors: Inoue, Jun, Fujiwara, Kyoko, Hamamoto, Hidetoshi, Kobayashi, Katsunori, Inazawa, Johji
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16.12.2020; American Society of Gene & Cell Therapy; Elsevier
• Subjects: EGFR-TKI; glutaminolysis; miRNA therapeutics; Original; skin cancer; topical treatment; miRNA therapeutics; skin cancer; EGFR-TKI; topical treatment; glutaminolysis
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2020.10.009

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) miR-634 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 miR-634 inhibited in vivo tumor growth without toxicity in a cSCC xenograft mouse model and a 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papilloma mouse model. Functional validation revealed that miR-634 overexpression reduced glutaminolysis by directly targeting ASCT2, a glutamine transporter. Furthermore, overexpression of miR-634 synergistically enhanced TKI-induced cytotoxicity by triggering severe energetic stress in vitro and in vivo. Thus, we propose that topical treatment with miR-634 ointment is a useful strategy for improving for EGFR TKI-based therapy for cSCC. [Display omitted] In this study, Inoue et al. demonstrate that topical treatment with miR-634 ointment improves the efficacy of EGFR tyrosine kinase inhibitor (TKI) for cutaneous squamous cell carcinoma (cSCC) by triggering severe energetic stress via concurrent targeting of multiple cytoprotective processes, including autophagy, antioxidative scavenger, anti-apoptosis, and glutaminolysis.