High TNF and NF-ĸB pathway dependency are associated with AZD5582 sensitivity in OSCC via CASP8-dependent apoptosis

Drug repurposing can accelerate the development of novel therapeutic strategies. Oral squamous cell carcinoma (OSCC) is prevalent in Asians and is associated with a poor prognosis. Here, we integrate newly generated sensitivity data for 339 anticancer drugs with genome-wide CRISPR‒Cas9 gene essentiality data for 21 cell lines mostly derived from Asian OSCC patients to identify drug repurposing candidates. We observe potent activity of AZD5582 (an antagonist of the inhibitor of apoptosis (IAP) family of proteins) in a subset of OSCC cells, which was associated with dependency on NF-ĸB pathway genes (RNF31, MAP3K7 and IKBKG). We confirm the on-target specificity and potency of AZD5582 in vitro and its ability to suppress cell growth in xenograft models. Furthermore, we identify tumor necrosis factor (TNF) as a key mediator of AZD5582 sensitivity in OSCC. CASP8-dependent apoptotic and CASP8-independent necroptotic cellular programs mediate AZD5582-induced cell death. In summary, through the systematic integration of pharmacological and CRISPR data, we identified a subset of OSCC with potent sensitivity to AZD5582 mediated through the NF-κB and TNF signalling pathways.