Abstract C042: Integrative analyses of CRISPR and drug screens identify a selective and potent compound for oral squamous cell carcinoma

Abstract

Mechanism-guided drug repurposing can accelerate the development of therapeutic strategies for oral squamous cell carcinoma (OSCC), which has an unmet clinical need. We integrated cell line sensitivity data for 339 anti-cancer drugs with genome-wide CRISPR-Cas9 screen gene essentiality data for 21 unique OSCC cell lines, derived primarily from Asian patients. We identified a significant correlation between AZD5582 sensitivity (an antagonist of the inhibitor of apoptosis (IAP) family proteins), and dependency on several members of the NF kappa-B pathway (RNF31, MAP3K7 and IKBKG). Dependent OSCC lines are more sensitive to AZD5582, with nanomolar range half-maximal inhibitory drug concentrations (IC50). We confirmed the on-target specificity and potency of AZD5582 in vitro and in vivo. Furthermore, AZD5582 sensitivity was associated with high levels of tumor necrosis factor (TNF) and either functional apoptotic or necroptotic pathways. In summary, our approach of integrating pharmacological and CRISPR screen data in a unique cohort of OSCC cell lines data has enabled the identification of specific dependencies and drug repurposing candidates.

Citation Format: Annie Wai Yeeng Chai, Yee Hua Tan, Shiyin Ooi, Pei San Yee, Shi Mun Yee, Howard Lightfoot, Syd Bathorpe, Mathew J Garnett, Sok Ching Cheong. Integrative analyses of CRISPR and drug screens identify a selective and potent compound for oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C042.