Data from Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts

• DOI: 10.1158/2767-9764.c.7128618
• Publication Date: 2024-03-19T14:27:58Z
• Authors: Yasuhiro Arakawa; Ukhyun Jo; Suresh Kumar; Nai-Yun Sun; Fathi Elloumi; Anish Thomas; Nitin Roper; Diana Grace Varghese; Naoko Takebe; Xiaohu Zhang; Michele Ceribelli; David O. Holland; Erin Beck; Zina Itkin; Crystal McKnight; Kelli M. Wilson; Jameson Travers; Carleen Klumpp-Th...; Craig J. Thomas; Chuong D. Hoang; Jonathan M. Herna...; Jaydira Del Rivero; Yves Pommier
• Keywords: Organoid; Carcinoma Cell

<div>Abstract<p>Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic ACC. An extensive drug screen was conducted compounds with potential activity against ACC cell lines. We further investigated mechanism action identified compound, TAK-243, its synergistic effects current therapeutics, efficacy in models including patient-derived organoids mouse xenografts. a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent TAK-243 inhibited protein ubiquitination cells, leading accumulation free ubiquitin, activation unfolded response, induction apoptosis. found be effluxed out cells by MDR1, efflux pump, did not require Schlafen 11 (<i>SLFN11</i>) expression activity. Combination therapies (e.g., mitotane, etoposide, cisplatin) produced or additive effects. In addition, highly BCL2 inhibitors (Navitoclax Venetoclax) preclinical organoids. The tumor suppressive Venetoclax were confirmed xenograft model. These findings provide evidence support initiation trial patients advanced-stage is promising option ACC, either as monotherapy combination existing inhibitors.</p>Significance:<p>ACC rare endocrine cancer poor prognosis options. report that active alone currently used mTOR models. Our results suggest implementation trials advanced ACC.</p></div>