GSE167481
Genome-wide synthetic lethal screen unveils novel CAIX – NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors.
Hypoxia is an important clinicopathological feature of solid tumours that limits response to therapy.  Carbonic Anhydrase IX (CAIX) is a hypoxia-induced, pH regulator that has emerged as a viable therapeutic target.  Targeting CAIX has demonstrated promise in difficult to treat preclinical models of breast pancreatic, melanoma and brain cancers when combined with chemotherapy and immunotherapy, however resistance ultimately develops and this mechanism is unclear.  Here we used an unbiased genome-wide synthetic lethal CRISPR knock-out screen in basal breast cancer cells to identify co-vulnerabilities and mechanisms of compensation for CA9 loss.  We identified a redox homeostasis network containing thioredoxin and the iron-sulfur cluster enzyme, cysteine desulfurase, NFS1, indicative of the critical importance of CAIX in this role. Overall design: Genome-wide CRISPR knock-out screen for synthetic lethal interactions of Carbonic anhydrase IX in hypoxic SUM159PT triple negative breast cancer cells. There are 4 samples done in duplicates.