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Abstract：
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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
目前转移性肾上腺皮质癌（ACC）的治疗方案疗效有限，尽管米托坦和细胞毒性剂的普遍使用。本研究旨在确定ACC的新治疗选择。进行广泛的药物筛选以鉴定对ACC细胞系具有潜在活性的化合物。我们进一步研究了鉴定的化合物的作用机制，TAK-243，其与当前ACC疗法的协同作用，及其在ACC模型中的功效，包括患者来源的类器官和小鼠异种移植物。TAK-243，一种临床泛素激活酶E1抑制剂，在ACC细胞系中显示出有效的活性。TAK-243抑制ACC细胞中的蛋白质泛素化，导致游离泛素的积累，激活未折叠的蛋白质反应（UPR），和诱导细胞凋亡。发现TAK-243通过药物外排泵MDR1流出细胞，并且不需要Schlafen11(SLFN11)表达其活性。TAK-243与当前ACC疗法的组合(例如，米托坦,依托泊苷,顺铂)产生协同或累加效应。此外,在包括患者来源的类器官的临床前ACC模型中，TAK-243与BCL2抑制剂（Navitoclax和Venetoclax）高度协同。在小鼠异种移植模型中进一步证实了TAK-243的肿瘤抑制作用及其与维奈托克的协同作用。这些发现提供了临床前证据，以支持在晚期肾上腺皮质癌患者中启动TAK-243的临床试验。TAK-243是ACC的一种有前途的潜在治疗选择，作为单一疗法或与现有疗法或BCL2抑制剂组合。
