Kathawala Rishil J, Espitia Claudia M, Jones Trace M, Islam Shariful, Gupta Pranav, Zhang Yun-Kai, Chen Zhe-Sheng, Carew Jennifer S, Nawrocki Steffan T
Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724, USA.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Cancers (Basel). 2020 Feb 12;12(2):429. doi: 10.3390/cancers12020429.
MLN4924 (pevonedistat) is a first-in-class NEDD8-activating enzyme (NAE) inhibitor in clinical trials for the treatment of solid tumors and hematologic malignancies. Despite the promising activity of MLN4924 observed in early trials, drug resistance has been noted in some patients. Identifying the underlying cause of treatment failure may help to better stratify patients that are most likely to benefit from this novel agent. Early preclinical studies revealed that the development of NAE mutations promotes resistance to MLN4924. However, these mutations have not been detected in patients that are relapsed/refractory to MLN4924, suggesting that other mechanisms are driving clinical resistance. To better understand the potential mechanisms of MLN4924 resistance, we generated MLN4924-resistant ovarian cancer cells. Interestingly, these cells did not develop mutations in NAE. Transcriptome analyses revealed that one of the most upregulated genes in resistant cells was . This result was validated by quantitative real-time PCR and immunoblotting. Importantly, the sensitivity of MLN4924-resistant cells was restored by lentiviral short hairpin RNA (shRNA) targeting . Further investigation using ABCG2-overexpressing NCI-H460/MX20 cells determined that these cells are resistant to the anticancer effects of MLN4924 and can be sensitized by co-treatment with the ABCG2 inhibitors YHO-13351 and fumitremorgin C. Finally, HEK293 models with overexpression of wild-type ABCG2 (R482) and variants (R482G and R482T) all demonstrated significant resistance to MLN4924 compared to wild-type cells. Overall, these findings define an important molecular resistance mechanism to MLN4924 and demonstrate that ABCG2 may be a useful clinical biomarker that predicts resistance to MLN4924 treatment.
MLN4924（pevonedistat）是一种一流的NEDD8激活酶（NAE）抑制剂，正在进行治疗实体瘤和血液系统恶性肿瘤的临床试验。尽管在早期试验中观察到MLN4924具有有前景的活性，但在一些患者中已注意到耐药性。确定治疗失败的根本原因可能有助于更好地对最有可能从这种新型药物中获益的患者进行分层。早期临床前研究表明，NAE突变的发生会促进对MLN4924的耐药性。然而，在对MLN4924复发/难治的患者中未检测到这些突变，这表明其他机制在驱动临床耐药性。为了更好地理解MLN4924耐药的潜在机制，我们生成了MLN4924耐药的卵巢癌细胞。有趣的是，这些细胞在NAE中未发生突变。转录组分析显示，耐药细胞中上调最明显的基因之一是 。这一结果通过定量实时PCR和免疫印迹得到验证。重要的是，通过靶向 的慢病毒短发夹RNA（shRNA）恢复了MLN4924耐药细胞的敏感性。使用过表达ABCG2的NCI-H460/MX20细胞进行的进一步研究确定，这些细胞对MLN4924的抗癌作用具有耐药性，并且可以通过与ABCG2抑制剂YHO-13351和烟曲霉震颤素C联合治疗而致敏。最后，与野生型细胞相比，过表达野生型ABCG2（R482）及其变体（R482G和R482T）的HEK293模型均表现出对MLN4924的显著耐药性。总体而言，这些发现确定了对MLN4924的一种重要分子耐药机制，并证明ABCG2可能是一种有用的临床生物标志物，可预测对MLN4924治疗的耐药性。
