Department of Surgery, Ellis Fischel Cancer Center, Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, Missouri.
Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri.
Clin Cancer Res. 2024 Sep 3;30(17):3855-3867. doi: 10.1158/1078-0432.CCR-23-3980.
Systemic treatments given to patients with non-small cell lung cancer (NSCLC) are often ineffective due to drug resistance. In the present study, we investigated patient-derived tumor organoids (PDTO) and matched tumor tissues from surgically treated patients with NSCLC to identify drug repurposing targets to overcome resistance toward standard-of-care platinum-based doublet chemotherapy.
PDTOs were established from 10 prospectively enrolled patients with non-metastatic NSCLC from resected tumors. PDTOs were compared with matched tumor tissues by histopathology/immunohistochemistry, whole exome sequencing, and transcriptome sequencing. PDTO growths and drug responses were determined by measuring 3D tumoroid volumes, cell viability, and proliferation/apoptosis. Differential gene expression analysis identified drug-repurposing targets. Validations were performed with internal/external data sets of patients with NSCLC. NSCLC cell lines were used for aldo-keto reductase 1B10 (AKR1B10) knockdown studies and xenograft models to determine the intratumoral bioavailability of epalrestat.
PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels.
PDTOs are efficient preclinical models recapitulating the tumor characteristics and are suitable for drug testing. AKR1B10 can be targeted by repurposing epalrestat to overcome chemoresistance in NSCLC. Epalrestat has the potential to advance to clinical trials in patients with drug-resistant NSCLC due to favorable toxicity, pharmacological profile, and bioavailability.
由于耐药性，给予非小细胞肺癌 (NSCLC) 患者的全身治疗往往无效。在本研究中，我们研究了来自接受手术治疗的 NSCLC 患者的患者衍生肿瘤类器官 (PDTO) 和匹配的肿瘤组织，以确定药物再利用靶点，以克服对标准护理铂类双联化疗的耐药性。
从 10 名接受过手术治疗的非转移性 NSCLC 患者的切除肿瘤中建立 PDTO。通过组织病理学/免疫组织化学、全外显子组测序和转录组测序比较 PDTO 与匹配的肿瘤组织。通过测量 3D 肿瘤球体体积、细胞活力和增殖/凋亡来确定 PDTO 生长和药物反应。差异基因表达分析确定了药物再利用靶点。使用 NSCLC 患者的内部/外部数据集进行验证。使用 NSCLC 细胞系进行醛酮还原酶 1B10 (AKR1B10) 敲低研究和异种移植模型，以确定依帕司他在肿瘤内的生物利用度。
PDTO 保留了匹配肿瘤组织的组织形态学和病理生物标志物表达、突变/转录组特征和细胞异质性。5 个 (50%) PDTO 对卡铂/紫杉醇有化疗耐药性。化疗耐药 PDTO 和匹配的肿瘤组织显示 AKR1B10 过表达。依帕司他是一种临床上用于治疗糖尿病多发性神经病的口服 AKR1B10 抑制剂，被重新用于克服 PDTO 的化疗耐药性。依帕司他在体内克服耐药性的疗效与肿瘤内依帕司他水平相对应。
PDTO 是有效的临床前模型，可重现肿瘤特征，适合药物测试。通过重新利用依帕司他来靶向 AKR1B10，可以克服 NSCLC 中的化疗耐药性。由于依帕司他具有良好的毒性、药理学特征和生物利用度，因此有可能在耐药性 NSCLC 患者中推进临床试验。
