Miller Aubrey L, Garcia Patrick L, Gamblin Tracy L, Vance Rebecca B, Yoon Karina J
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294 USA.
Cancer Drug Resist. 2020;3(3):572-585. doi: 10.20517/cdr.2020.35. Epub 2020 Aug 7.
Gemcitabine is a frontline agent for locally-advanced and metastatic pancreatic ductal adenocarcinoma (PDAC), but neither gemcitabine alone nor in combination produces durable remissions of this tumor type. We developed three PDAC patient-derived xenograft (PDX) models with gemcitabine resistance (gemR) acquired , with which to identify mechanisms of resistance relevant to drug exposure and to evaluate novel therapies.
Mice bearing independently-derived PDXs received 100 mg/kg gemcitabine once or twice weekly. Tumors initially responded, but regrew on treatment and were designated gemR. We used immunohistochemistry to compare expression of proteins previously associated with gemcitabine resistance [ribonucleotide reductase subunit M1 (RRM1), RRM2, human concentrative nucleoside transporter 1 (hCNT1), human equilibrative nucleoside transporter 1 (hENT1), cytidine deaminase (CDA), and deoxycytidine kinase (dCK)] in gemR and respective gemcitabine-naive parental tumors.
Parental and gemR tumors did not differ in tumor cell morphology, amount of tumor-associated stroma, or expression of stem cell markers. No consistent pattern of expression of the six gemR marker proteins was observed among the models. Increases in RRM1 and CDA were consistent with -derived gemR models. However, rather than the expected decreases of hCNT1, hENT1, and dCK, gemR tumors expressed no change in or higher levels of these gemR marker proteins than parental tumors.
These models are the first PDAC PDX models with gemcitabine resistance acquired . The data indicate that mechanisms identified in models with resistance acquired are unlikely to be the predominant mechanisms when resistance is acquired . Ongoing work focuses on characterizing unidentified mechanisms of gemR and on identifying agents with anti-tumor efficacy in these gemR models.
吉西他滨是局部晚期和转移性胰腺导管腺癌（PDAC）的一线治疗药物，但无论是单独使用吉西他滨还是联合其他药物，都无法使这种肿瘤类型实现持久缓解。我们构建了三种获得吉西他滨耐药性（gemR）的PDAC患者来源异种移植（PDX）模型，用于确定与药物暴露相关的耐药机制，并评估新型治疗方法。
携带独立来源PDX的小鼠每周接受一次或两次100mg/kg吉西他滨治疗。肿瘤最初有反应，但在治疗过程中复发，被认定为gemR。我们使用免疫组织化学方法比较了gemR肿瘤和各自未接受过吉西他滨治疗的亲本肿瘤中，先前与吉西他滨耐药相关的蛋白质[核糖核苷酸还原酶亚基M1（RRM1）、RRM2、人浓缩核苷转运体1（hCNT1）、人平衡核苷转运体1（hENT1）、胞苷脱氨酶（CDA）和脱氧胞苷激酶（dCK）]的表达情况。
亲本肿瘤和gemR肿瘤在肿瘤细胞形态、肿瘤相关基质数量或干细胞标志物表达方面没有差异。在这些模型中，未观察到六种gemR标志物蛋白一致的表达模式。RRM1和CDA的增加与获得性gemR模型一致。然而，与预期的hCNT1、hENT1和dCK水平降低相反，gemR肿瘤中这些gemR标志物蛋白的表达与亲本肿瘤相比没有变化或更高。
这些模型是首批获得吉西他滨耐药性 的PDAC PDX模型。数据表明，在获得性耐药模型中确定的机制不太可能是获得耐药性时的主要机制。正在进行的工作重点是表征未确定的gemR机制，并在这些gemR模型中鉴定具有抗肿瘤疗效的药物。
