Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively induces death of mTORC1 hyperactive cells

摘要: // Elaine A. Dunlop 1 , Charlotte E. Johnson Marie Wiltshire Rachel J. Errington and Andrew R. Tee Division of Cancer Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK Correspondence to: Tee, email: Keywords : mTORC1, TSC, therapy, nelfinavir, cell death Received February 28, 2017 Accepted March 03, Published 15, Abstract Uncontrolled growth in Tuberous Sclerosis Complex occurs due to inappropriate activation mechanistic (mammalian) target rapamycin complex (mTORC1). The current rapamycin, produced promising clinical trial results, but patient tumours regrow if treatment is discontinued, revealing has cytostatic properties rather than a cytotoxic effect. Taking advantage the enhanced levels endoplasmic reticulum (ER) stress present TSC2 -null cells, we investigated drug combinations producing response. We found nelfinavir salinomycin combination specifically killed -deficient, mTORC1 hyperactive cells. Cytotoxicity was rescued by reducing protein synthesis, either through inhibition or cycloheximide treatment. This indicates that targets cells tipping homeostasis balance already metabolically stressed -deficient favour death. Furthermore, this also inhibited tumour formation models caused spheroid 3D culture. Importantly, assay could differentiate agent, from nelfinavir/salinomycin combination. Sporadic cancer lines with signalling were susceptible work pathway an attractive therapeutic both mTORC1-driven sporadic cancers.