Targeting ErbB3 and Cellular NADPH/NADP+ Abundance Sensitizes Cutaneous Melanomas to Ferroptosis Inducers

Melanoma is a serious health challenge. Ferroptosis is aregulated form of oxidative cell death that shows varied efficacy inmelanoma. We aimed to better understand the molecular basis for thisdifferential ferroptosis sensitivity. Wefind that elevated expression ofErbB3 (V-Erb-B2 Avian Erythroblastic Leukemia Viral OncogeneHomologue 3) associates with ferroptosis resistance and that ErbB3knockdown sensitizes to ferroptosis inducers. ErbB3 depletion also promotes a marked reduction in the cellular ratio of GSH/GSSG(reduced/oxidized glutathione) and that of NADPH/NADP+(reduced/oxidized nicotinamide adenine dinucleotide phosphate),together with an increase in the abundance of the lipid peroxidation product malondialdehyde (MDA). We identify several smallmolecule inhibitors targeting ErbB3 signaling pathways that also reduce the NADPH/NADP+and GSH/GSSG ratios, concomitantlysensitizing the melanomas to ferroptosis activators. Thesefindings point to a previously unrecognized role of ErbB3 in ferroptosissensitivity and provide new insight into pathways that regulate this cell death process.

Automated summary

This study reveals the association between elevated expression of ErbB3 and resistance to ferroptosis in melanoma. Knockdown of ErbB3 sensitizes melanomas to ferroptosis inducers and leads to a reduction in the cellular ratio of GSH/GSSG and NADPH/NADP+. The study also identifies small molecule inhibitors targeting ErbB3 signaling pathways that sensitize melanomas to ferroptosis activators, providing new insights into the regulation of this cell death process.