American Association for Cancer Research
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FIGURE 7 from Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts

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posted on 2024-03-19, 14:20 authored by 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-Thomas, Craig J. Thomas, Chuong D. Hoang, Jonathan M. Hernandez, Jaydira Del Rivero, Yves Pommier

Synergy between TAK-243 and Venetoclax in organoids generated from patient-derived xenograft (PDXO). A, Representative brightfield images of PDXOs (20x magnification, scale bar 50 µm). B, Phenotypic characteristics of PDXOs. Expression of biomarkers routinely used to diagnose ACC, including inhibin-α, SF-1, INSM-1, and β-catenin in ACC-PDX-derived organoids using immunofluorescence assay. C, Top: The indicated ACC PDXOs were treated with TAK-243 with or without Venetoclax for 72 hours. Bottom: Plots of the corresponding CI values.


HHS | NIH | National Cancer Institute (NCI)

Japanese Society of Clinical Pharmacology and Therapeutics (JSCPT)

HHS | NIH | National Center for Advancing Translational Sciences (NCATS)



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

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