Bucillamine Prevents Afatinib-Mediated Inhibition of Epidermal Growth Factor Receptor Signaling

Area of Science:

• Pharmacology
• Oncology
• Toxicology

Background:

• Molecular targeting therapies, like anti-EGFR treatments, can cause adverse effects such as skin rash, hindering treatment continuation.
• Skin symptoms in EGFR inhibition correlate with patient survival, highlighting the need to manage these side effects for better clinical outcomes.

Purpose of the Study:

• To propose a novel strategy for reducing adverse effects from EGFR-tyrosine kinase inhibitors (TKIs) in non-tumorous organs.
• To identify potential drug candidates for managing EGFR-TKI-induced side effects by repositioning approved medicines.
• To develop and utilize a zebrafish model for screening chemical quenchers of EGFR-TKIs.

Main Methods:

• A zebrafish model was developed to evaluate chemical quenchers of afatinib, an irreversible EGFR-TKI.
• The model scored the inhibition of afatinib-induced hyperformation of lateral line neuromasts in zebrafish larvae.
• In vitro assays were used to confirm the inhibitory activity of identified quenchers on TKI activity.

Main Results:

• Bucillamine, an antirheumatic drug, was identified as an afatinib quencher in the zebrafish model.
• Bucillamine demonstrated inhibition of TKI activity in vitro.
• Bucillamine restored EGFR autophosphorylation and downstream signaling in afatinib-treated A431 cells, indicating its potential to counteract EGFR-TKI effects.

Conclusions:

• Topical bucillamine shows potential as a reliever for irreversible EGFR-TKI-induced skin rash.
• The developed zebrafish model is applicable for screening quenchers for various anti-EGFR therapies, including reversible TKIs and biologics.