Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
J Exp Clin Cancer Res. 2023 Apr 26;42(1):100. doi: 10.1186/s13046-023-02678-1.
Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease. Elevated MYC expression is common in SCLC and has been associated with platinum resistance. This study evaluates the capacity of MYC to drive platinum resistance and through screening identifies a drug capable of reducing MYC expression and overcoming resistance.
Elevated MYC expression following the acquisition of platinum resistance in vitro and in vivo was assessed. Moreover, the capacity of enforced MYC expression to drive platinum resistance was defined in SCLC cell lines and in a genetically engineered mouse model that expresses MYC specifically in lung tumors. High throughput drug screening was used to identify drugs able to kill MYC-expressing, platinum resistant cell lines. The capacity of this drug to treat SCLC was defined in vivo in both transplant models using cell lines and patient derived xenografts and in combination with platinum and etoposide chemotherapy in an autochthonous mouse model of platinum resistant SCLC.
MYC expression is elevated following the acquisition of platinum resistance and constitutively high MYC expression drives platinum resistance in vitro and in vivo. We show that fimepinostat decreases MYC expression and that it is an effective single agent treatment for SCLC in vitro and in vivo. Indeed, fimepinostat is as effective as platinum-etoposide treatment in vivo. Importantly, when combined with platinum and etoposide, fimepinostat achieves a significant increase in survival.
MYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.
小细胞肺癌（SCLC）是一种侵袭性神经内分泌癌，总生存率不到 5%（Zimmerman 等人，J Thor Oncol 14：768-83，2019）。患者通常对一线铂类双联化疗有反应，但几乎都因耐药性疾病而复发。MYC 表达升高在 SCLC 中很常见，并与铂类耐药有关。本研究评估了 MYC 驱动铂类耐药的能力，并通过筛选确定了一种能够降低 MYC 表达并克服耐药性的药物。
评估了体外和体内获得铂类耐药后 MYC 表达的升高。此外，还定义了强制表达 MYC 驱动 SCLC 细胞系和专门在肺肿瘤中表达 MYC 的基因工程小鼠模型中的铂类耐药的能力。高通量药物筛选用于鉴定能够杀死表达 MYC 和铂类耐药的细胞系的药物。该药物在体内使用细胞系和患者来源的异种移植物在移植模型中以及与铂类和依托泊苷化疗联合在铂类耐药 SCLC 的自发模型中治疗 SCLC 的能力进行了定义。
MYC 表达在获得铂类耐药后升高，并且持续高 MYC 表达驱动体外和体内的铂类耐药。我们表明，非那司提能够降低 MYC 表达，并且在体外和体内都是 SCLC 的有效单药治疗。事实上，非那司提在体内与铂类-依托泊苷治疗一样有效。重要的是，当与铂类和依托泊苷联合使用时，非那司提可显著提高生存率。
MYC 是 SCLC 铂类耐药的有力驱动因素，可有效用非那司提治疗。
