Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia.
Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, 66100, Chieti, Italy.
J Exp Clin Cancer Res. 2019 Aug 5;38(1):312. doi: 10.1186/s13046-019-1308-7.
Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive and lethal disease, lacking effective therapeutic approaches. Available therapies only marginally prolong patient survival and are frequently coupled with severe adverse events. It is therefore pivotal to investigate novel and safe pharmacological approaches. We have recently identified the ABC transporter, ABCC3, whose expression is dependent on mutation of TP53, as a novel target in PDAC. ABCC3-mediated regulation of PDAC cell proliferation and tumour growth in vivo was demonstrated and was shown to be conferred by upregulation of STAT3 signalling and regulation of apoptosis.
To verify the potential of ABCC3 as a pharmacological target, a small molecule inhibitor of ABCC3, referred to here as MCI-715, was designed. In vitro assays were performed to assess the effects of ABCC3 inhibition on anchorage-dependent and anchorage-independent PDAC cell growth. The impact of ABCC3 inhibition on specific signalling pathways was verified by Western blotting. The potential of targeting ABCC3 with MCI-715 to counteract PDAC progression was additionally tested in several animal models of PDAC, including xenograft mouse models and transgenic mouse model of PDAC.
Using both mouse models and human cell lines of PDAC, we show that the pharmacological inhibition of ABCC3 significantly decreased PDAC cell proliferation and clonal expansion in vitro and in vivo, remarkably slowing tumour growth in mice xenografts and patient-derived xenografts and increasing the survival rate in a transgenic mouse model. Furthermore, we show that stromal cells in pancreatic tumours, which actively participate in PDAC progression, are enriched for ABCC3, and that its inhibition may contribute to stroma reprogramming.
Our results indicate that ABCC3 inhibition with MCI-715 demonstrated strong antitumor activity and is well tolerated, which leads us to conclude that ABCC3 inhibition is a novel and promising therapeutic strategy for a considerable cohort of patients with pancreatic cancer.
胰腺导管腺癌（PDAC）是一种侵袭性和致命性疾病，缺乏有效的治疗方法。现有的治疗方法只能略微延长患者的生存时间，并且常常伴有严重的不良反应。因此，研究新的安全药理学方法至关重要。我们最近发现，ABCC3 是一种 ABC 转运蛋白，其表达依赖于 TP53 的突变，是 PDAC 的一个新靶点。ABCC3 介导的 PDAC 细胞增殖和体内肿瘤生长的调节作用已得到证实，并被证明是通过上调 STAT3 信号和调节细胞凋亡来实现的。
为了验证 ABCC3 作为药理学靶点的潜力，设计了一种 ABCC3 的小分子抑制剂，这里称为 MCI-715。进行了体外测定以评估 ABCC3 抑制对锚定依赖性和非锚定依赖性 PDAC 细胞生长的影响。通过 Western 印迹验证了 ABCC3 抑制对特定信号通路的影响。此外，还在几种 PDAC 动物模型中测试了用 MCI-715 靶向 ABCC3 以对抗 PDAC 进展的潜力，包括异种移植小鼠模型和 PDAC 转基因小鼠模型。
使用小鼠模型和 PDAC 的人细胞系，我们表明 ABCC3 的药理学抑制显著降低了 PDAC 细胞在体外和体内的增殖和克隆扩张，显著减缓了小鼠异种移植和患者来源的异种移植中的肿瘤生长，并增加了转基因小鼠模型中的存活率。此外，我们表明胰腺肿瘤中的基质细胞，它们积极参与 PDAC 的进展，富含 ABCC3，其抑制可能有助于基质重编程。
我们的结果表明，用 MCI-715 抑制 ABCC3 表现出强烈的抗肿瘤活性且耐受性良好，这使我们得出结论，ABCC3 抑制是一种针对相当一部分胰腺癌患者的新的有前途的治疗策略。
