Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma.
Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma.
复制标题
溴和末端结构域抑制剂可诱导胰腺导管腺癌中的线粒体应激。
DOI：
10.1158/1535-7163.mct-23-0149
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发表时间：
2023
影响因子：
5.7
通讯作者：
Glazer,EvanS
中科院分区：
文献类型：
--
作者：
Rana,Manjul;Kansal,RitaG;Bisunke,Bijay;Fang,Jie;Shibata,David;Bajwa,Amandeep;Yang,Jun;Glazer,EvanS
为胰腺导管腺癌（PDAC）患者确定新的、独特的和个性化的分子靶点仍然是改变致命性肿瘤生物学的最大挑战。溴和末端外结构域（BET）蛋白以非经典方式被TGFβ激活，TGF β是PDAC肿瘤微环境（TME）中普遍存在的细胞因子。我们假设BET抑制剂（BETi）代表了一类通过新机制攻击PDAC肿瘤的新药物。使用患者和同系小鼠模型的组合，我们研究了BETi药物BMS-986158对细胞增殖、类器官生长、细胞周期进展和线粒体代谢破坏的影响。对这些进行了独立研究，并与标准细胞毒性化疗（吉西他滨+紫杉醇[GemPTX]）联合研究。BMS-986158以剂量依赖性方式降低多种PDAC细胞系的细胞活力和增殖，与细胞毒性化疗联合使用时更是如此（P< 0.0001）。我们发现BMS-986158降低人和鼠PDAC类器官生长（P< 0.001），并伴随细胞周期相关扰动，导致细胞周期停滞。BMS-986158破坏正常的癌症依赖性线粒体功能，通过功能失调的细胞呼吸、质子泄漏和ATP产生导致线粒体代谢异常和应激。我们证明了BETi单独和与全身细胞毒性化疗联合诱导代谢线粒体功能障碍、消除PDAC进展和增殖的机制和功能数据。这种新方法改善了PDAC患者的治疗窗口，并提供了另一种不同于靶向癌细胞生物能量学的细胞毒性化疗的治疗方法。
Identifying novel, unique, and personalized molecular targets for patients with pancreatic ductal adenocarcinoma (PDAC) remains the greatest challenge in altering the biology of fatal tumors. Bromo- and extra-terminal domain (BET) proteins are activated in a noncanonical fashion by TGFβ, a ubiquitous cytokine in the PDAC tumor microenvironment (TME). We hypothesized that BET inhibitors (BETi) represent a new class of drugs that attack PDAC tumors via a novel mechanism. Using a combination of patient and syngeneic murine models, we investigated the effects of the BETi drug BMS-986158 on cellular proliferation, organoid growth, cell-cycle progression, and mitochondrial metabolic disruption. These were investigated independently and in combination with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX]). BMS-986158 reduced cell viability and proliferation across multiple PDAC cell lines in a dose-dependent manner, even more so in combination with cytotoxic chemotherapy (P< 0.0001). We found that BMS-986158 reduced both human and murine PDAC organoid growth (P< 0.001), with associated perturbations in the cell cycle leading to cell-cycle arrest. BMS-986158 disrupts normal cancer-dependent mitochondrial function, leading to aberrant mitochondrial metabolism and stress via dysfunctional cellular respiration, proton leakage, and ATP production. We demonstrated mechanistic and functional data that BETi induces metabolic mitochondrial dysfunction, abrogating PDAC progression and proliferation, alone and in combination with systemic cytotoxic chemotherapies. This novel approach improves the therapeutic window in patients with PDAC and offers another treatment approach distinct from cytotoxic chemotherapy that targets cancer cell bioenergetics.