Preventing skin toxicities induced by EGFR inhibitors by topically blocking drug-receptor interactions

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.

Topical JAK inhibition ameliorates EGFR inhibitor–induced rash in rodents and humans

“…It would be better to treat adverse events at their sites with minimal systemic exposure, thereby preserving the antitumor effects and without inducing additional systemic effects (44,45). On the basis of our results, topical JAKi showed limited systemic exposure, with no adverse effects on the antitumor potency of EGFRi in vivo, and no increased risk of bacterial and viral infections was observed during the experiment, suggesting that topical JAKi administration may be a safe regimen for treating EGFRi-induced skin rash.…”