Sharon Merims - Preventing skin toxicities induced by EGFR inhibitors by topically blocking drug-receptor interactions
Preventing skin toxicities induced by EGFR inhibitors by topically blocking drug-receptor interactions
https://www.science.org/doi/10.1126/scitranslmed.abo0684
Sci Transl Med 2023 Jun 7;15(699): eabo0684.
doi: 10.1126/scitranslmed. abo0684. Epub 2023 Jun 7.
Nethanel Friedman 1, Liza Weinstein-Fudim 2 3, Yelena Mostinski 2, Jhonatan Elia 4, Sherri Cohen 2, Eliana Steinberg 1, Shoshana Frankenburg 2 5 6, Tamar Peretz 2, Galit Eisenberg 2 5 6, Michal Lotem 2 5 6, Ofra Benny 1, Sharon Merims 2 5 6
1 Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
2 Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem 91120, Israel.
3 Laboratory of Teratology, Department of Medical Neurobiology, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem 91120, Israel.
4 Department of Plastic and Reconstructive Surgery, Hadassah Medical Center, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem 91120, Israel.
5 Wohl Institute for Translational Medicine, Hadassah Medical Organization, Jerusalem 91120, Israel.
6 Hadassah Cancer Research Institute (HCRI), Jerusalem 91120, Israel.
Abstract
Epidermal growth factor receptor (EGFR) inhibitors are used to treat many advanced-stage epithelial cancers but induce severe skin toxicities in most treated patients. These side effects lead to a deterioration in the quality of life of the patients and compromise the anticancer treatment. Current treatment strategies for these skin toxicities focus on symptom reduction rather than preventing the initial trigger that causes the toxicity. In this study, we developed a compound and method for treating “on-target” skin toxicity by blocking the drug at the site of toxicity without reducing the systemic dose reaching the tumor. We first screened for small molecules that effectively blocked the binding of anti-EGFR monoclonal antibodies to EGFR and identified a potential candidate, SDT-011. In silico docking predicted that SDT-011 interacted with the same residues on EGFR found to be important for the binding of EGFR inhibitors cetuximab and panitumumab. Binding of SDT-011 to EGFR reduced the binding affinity of cetuximab to EGFR and could reactivate EGFR signaling in keratinocyte cell lines, ex vivo cetuximab-treated whole human skin, and A431-injected mice. Specific small molecules were topically applied and were delivered via a slow-release system derived from biodegradable nanoparticles that penetrate the hair follicles and sebaceous glands, within which EGFR is highly expressed. Our approach has the potential to reduce skin toxicity caused by EGFR inhibitors.