Abstract 552: Non-canonical disulfide isomerases are strongly selective, understudied targets for cancer therapy

Abstract

Abstract A major challenge in cancer therapy is the identification of drug targets that are essential for cancer cells but not non-transformed cells. The Broad Institute’s Dependency Map (DepMap) evaluates whether knocking down or knocking out expression of specific genes is “strongly selective” against subsets of cancer cells, in contrast with genes that are “common essential.” Of the 22 human Protein Disulfide Isomerases (PDIs), only four, ERp44, TMX1, AGR2, and AGR3, were identified as strongly selective in the DepMap. Importantly, our team previously identified ERp44, AGR2, and AGR3 as targets of bicyclic thiosulfonate compounds termed Disulfide bond Disrupting Agents (DDAs). DDAs exhibit striking anti-cancer activity in xenograft tumor studies. DDA treatment of cancer cells blocks ERp44, AGR2, and AGR3 active site Cys residues, ablating their catalytic activity and binding to client proteins. Evaluation of cancer cell lines predicted to be sensitive to DDAs, based on their AGR2, AGR3, or ERp44 dependence, accurately predicts DDA sensitivity. Cell lines from a variety of tumor types exhibit AGR2, AGR3, or ERp44 dependencies. Our previous work identified HER-family members (i.e., EGFR, HER2, and HER3) and TRAIL receptors (Death Receptors 4 and 5) as important clients of DDA-sensitive PDIs in breast cancer cells, but it was unknown if these observations extend to other tumor types. Initial studies indicate that AGR2 DepMap dependencies are a strong predictor of sensitivity of cancer cells to DDAs, irrespective of their site of origin. It will be important in future studies to determine what the key client proteins for these DDA-sensitive PDIs are and whether they vary across tumor types. Citation Format: Mary E. Law, Zaafir M. Dulloo, Elham Yaaghubi, Grace M. Alexandrow, Bianca Forsyth, Hanyu Su, Ronald K. Castellano, Brian K. Law. Non-canonical disulfide isomerases are strongly selective, understudied targets for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 552.