1. ERK mediates interferon gamma-induced melanoma cell death
- Author
-
Champhekar, Ameya, Heymans, Rachel, Saco, Justin, Turon Font, Guillem, Gonzalez, Cynthia, Gao, Anne, Pham, John, Lee, June, Maryoung, Ryan, Medina, Egmidio, Campbell, Katie M, Karin, Daniel, Austin, David, Damioseaux, Robert, and Ribas, Antoni
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Cancer ,Genetics ,Human Genome ,Vaccine Related ,5.1 Pharmaceuticals ,Aetiology ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,Humans ,Melanoma ,Interferon-gamma ,Skin Neoplasms ,Cell Line ,Tumor ,Proto-Oncogene Proteins B-raf ,Apoptosis ,IFN gamma ,ERK signaling ,Tumor growth inhibition ,Stress response ,IFNγ ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
BackgroundInterferon-gamma (IFNγ) 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.MethodsWe performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death.ResultsWe show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 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.ConclusionsOur results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.
- Published
- 2023