ERK mediates interferon gamma-induced melanoma cell death

Background Interferon-gamma (IFN gamma) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway. Methods We performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFN gamma-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFN gamma exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFN gamma-mediated cell death. Results We show that IFN gamma signaling activated ERK. Blocking ERK activation rescued IFN gamma-mediated apoptosis in 17 of 23 (similar to 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins. Conclusions Our results provide a new understanding of the IFN gamma growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.

Automated summary

Through chemical genomics and whole genome targeting CRISPR/Cas9 screens, researchers have identified essential nodes in the IFN_gamma-mediated growth inhibition pathway and confirmed the involvement of cell death pathways through transcriptomic profiling and live imaging experiments. The activation of ERK signaling induces a stress response that leads to apoptosis via the activity of DR5 and NOXA proteins.